REF_ID	PDC_ID	Indication_Name	animal model	PDC_activity_Level	Receptor_expression	efficacy_type	efficacy_Value_d	efficacy_Unit	Clinical_trial_identification	Clinical_trial_description	Clinical_trial_status	Patients_enrolled	pdc_cell_disease	pdc_cell_name	Half life period	Cell_Uptake	Administration_Times	Administration_Dosage	Evaluation_method	Method_description	PDC_MOA
REF00054	PDC_00027	Functioning pancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	18.1	months	.	.	.	Patients with functioning pancreatic neuroendocrine tumors.	.	.	.	.	4 cycles	7.4 GBq/cycle	.	"Subacute hematological toxicity, grade 3 or 4 occurred in 4 patients (12%) and a hormonal crisis in 3 patients (9%). PRRT resulted in partial or complete response in 59% of patients and the disease control rate was 78% in patients with baseline progression. 71% of patients with uncontrolled symptoms had a reduction of symptoms and a more than 80% decrease of circulating hormone levels was measured during follow-up. After PRRT, median progression-free survival was 18.1 months (interquartile range: 3.3 to 35.7) with a concurrent increase in QOL."	.
REF00068	PDC_00241	Hepatocellular carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	205	days	.	.	.	Patients with hepatocellular carcinoma who progressed on or after treatment with sorafenib or intolerant of sorafenib.	.	.	.	.	"Days 1, 2, and 3 of a 28-day cycle"	40 mg/m<sup>2</sup>	.	"The median TTP was 134.0 days, median PFS was 129.0 days, and median OS was 205.0 days."	.
REF00068	PDC_00241	Hepatocellular carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	129	days	.	.	.	Patients with hepatocellular carcinoma who progressed on or after treatment with sorafenib or intolerant of sorafenib.	.	.	.	.	"Days 1, 2, and 3 of a 28-day cycle"	40 mg/m<sup>2</sup>	.	"The median TTP was 134.0 days, median PFS was 129.0 days, and median OS was 205.0 days."	.
REF00571	PDC_01077	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Haemozoin inhibition	50%-75%	.	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	.	.	.	"The capacity of test compounds 8 and 9 to inhibit heme polymerization in vitro was assessed by previously reported methods, given in detail under Experimental. The assays were run in 96-well microplates, where negative controls (water, DMSO) and positive controls (1 mM CQ) were included. Test compounds were assayed at 1 mM and data are given in Table 1. Interestingly, the dipeptide spacer was required to block heme polymerization, i.e., while HECINs 9 were not active, HEDICINs 8 displayed variable inhibitory efficiencies, with four out of the twelve compounds (8b, 8e, 8j and 8l) highly active (i.e., comparable to the reference drug, CQ). Though no clear trend could be established regarding stereoelectronic properties of the aryl substituent in compounds 8, it was clear that: (i) hydrogen (i.e., absence of a substituent) or halogens in the para position were detrimental for activity, whereas (ii) nitrogenated groups at either the ortho (8j, o-NO2) or the para (8e, p-NH2; 8l, p-NO2) position of the aryl ring was beneficial, but (iii) detrimental if placed in the meta position (8k, m-NO2). Furthermore, while small alkyl groups in para (8b, p-Me) were advantageous, bulkier groups as in 8c (p-iPr) led to complete loss of activity. Thus, replacement of CQ's aliphatic chain by an adequate dipeptidyl-cinnamoyl moiety as in 8b, 8e, 8j and 8l appears to preserve the parent drug's ability to inhibit hemozoin formation, suggesting that these novel compounds could be promising leads for new CQ surrogates."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01072	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Haemozoin inhibition	50%-75%	.	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	.	.	.	"The capacity of test compounds 8 and 9 to inhibit heme polymerization in vitro was assessed by previously reported methods, given in detail under Experimental. The assays were run in 96-well microplates, where negative controls (water, DMSO) and positive controls (1 mM CQ) were included. Test compounds were assayed at 1 mM and data are given in Table 1. Interestingly, the dipeptide spacer was required to block heme polymerization, i.e., while HECINs 9 were not active, HEDICINs 8 displayed variable inhibitory efficiencies, with four out of the twelve compounds (8b, 8e, 8j and 8l) highly active (i.e., comparable to the reference drug, CQ). Though no clear trend could be established regarding stereoelectronic properties of the aryl substituent in compounds 8, it was clear that: (i) hydrogen (i.e., absence of a substituent) or halogens in the para position were detrimental for activity, whereas (ii) nitrogenated groups at either the ortho (8j, o-NO2) or the para (8e, p-NH2; 8l, p-NO2) position of the aryl ring was beneficial, but (iii) detrimental if placed in the meta position (8k, m-NO2). Furthermore, while small alkyl groups in para (8b, p-Me) were advantageous, bulkier groups as in 8c (p-iPr) led to complete loss of activity. Thus, replacement of CQ's aliphatic chain by an adequate dipeptidyl-cinnamoyl moiety as in 8b, 8e, 8j and 8l appears to preserve the parent drug's ability to inhibit hemozoin formation, suggesting that these novel compounds could be promising leads for new CQ surrogates."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00094	PDC_00029	Metastatic castration-resistant prostate cancer	Men with metastatic castrate-resistant prostate cancer.	Identified from the Human Clinical Data	High Expreesion	ALP level hazard ratio	1.1	.	.	.	.	.	.	.	.	.	After receiving 177lu-psma-617 treatment	.	.	"This analysis identified FDG-positive tumour volume (FDGvol; HR 2.6; 95% CI, 1.4-4.8), mean intensity of PSMA-avid tumour uptake (PSMAmean; HR 0.89; 95% CI, 0.8-0.98), bone scan index (BSI; HR 2.3; 95% CI, 1.2-4.4), ALP (HR 1.1; 95% CI, 1-1.2) and LDH (HR 1.2; 95% CI, 1-1.8) as biomarkers prognostic of overall survival."	.
REF00094	PDC_00029	Metastatic castration-resistant prostate cancer	Men with metastatic castrate-resistant prostate cancer.	Identified from the Human Clinical Data	High Expreesion	Bone scan index hazard ratio	2.3	.	.	.	.	.	.	.	.	.	After receiving 177lu-psma-617 treatment	.	.	"This analysis identified FDG-positive tumour volume (FDGvol; HR 2.6; 95% CI, 1.4-4.8), mean intensity of PSMA-avid tumour uptake (PSMAmean; HR 0.89; 95% CI, 0.8-0.98), bone scan index (BSI; HR 2.3; 95% CI, 1.2-4.4), ALP (HR 1.1; 95% CI, 1-1.2) and LDH (HR 1.2; 95% CI, 1-1.7) as biomarkers prognostic of overall survival."	.
REF00094	PDC_00029	Metastatic castration-resistant prostate cancer	Men with metastatic castrate-resistant prostate cancer.	Identified from the Human Clinical Data	High Expreesion	FDG-positive molecular tumour volume hazard ratio	2.6	.	.	.	.	.	.	.	.	.	After receiving 177lu-psma-617 treatment	.	.	"This analysis identified FDG-positive tumour volume (FDGvol; HR 2.6; 95% CI, 1.4-4.8), mean intensity of PSMA-avid tumour uptake (PSMAmean; HR 0.89; 95% CI, 0.8-0.98), bone scan index (BSI; HR 2.3; 95% CI, 1.2-4.4), ALP (HR 1.1; 95% CI, 1-1.2) and LDH (HR 1.2; 95% CI, 1-1.5) as biomarkers prognostic of overall survival."	.
REF00094	PDC_00029	Metastatic castration-resistant prostate cancer	Men with metastatic castrate-resistant prostate cancer.	Identified from the Human Clinical Data	High Expreesion	Mean intensity of PSMA tumour uptake hazard ratio	0.89	.	.	.	.	.	.	.	.	.	After receiving 177lu-psma-617 treatment	.	.	"This analysis identified FDG-positive tumour volume (FDGvol; HR 2.6; 95% CI, 1.4-4.8), mean intensity of PSMA-avid tumour uptake (PSMAmean; HR 0.89; 95% CI, 0.8-0.98), bone scan index (BSI; HR 2.3; 95% CI, 1.2-4.4), ALP (HR 1.1; 95% CI, 1-1.2) and LDH (HR 1.2; 95% CI, 1-1.6) as biomarkers prognostic of overall survival."	.
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Delayed disease progression hazard ratio	0.63	.	NCT03392428	"This open label, randomised, stratified, 2-arm, multicentre, phase 2 trial aims to determine the activity and safety of Lu-PSMA vs cabazitaxel in men with progressive metastatic castration resistant prostate cancer"	Phase 2	65 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	&le;6 cycles every 6 weeks	6.0-8.5 GBq	.	"65 of 99 patients treated with lutetium Lu 177 vipivotide tetraxetan 6.0-8.5 GBq every 6 weeks for up to 6 cycles (n = 99) compared with 37 of 101 patients receiving cabazitaxel 20 mg/m<sup>2</sup> every 3 weeks for up to 10 cycles achieved a PSA reduction of &ge; 50% from baseline [66% vs 37%; treatment difference 29% (95% CI 16-42); p < 0.0001 (ITT analysis)]. Lutetium Lu 177 vipivotide tetraxetan also delayed disease progression [HR 0.63 (95% CI 0.46-0.86;) p = 0.0028], radiographic progression [0.64 (95% CI 0.46-0.88); p = 0.0070] and PSA PFS [0.60 (95% CI 0.44-0.83); p = 0.0017] compared with cabazitaxel."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00119	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median time to pain progression	8.3 months	months	NCT03511664	The primary objective of this study was to compare the two alternate primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) in patients with progressive prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who received 177Lu-PSMA-617 in addition to best supportive/best standard of care (BSC/BSoC) versus patients treated with best supportive/best standard of care alone.	Phase 3	Patients with metastatic castration-resistant prostate cancer treated with LuPSMA between December 2014 and July 2019.	.	.	.	.	.	.	.	"Median baseline PSA was 1000 (interquartile range 431-2151) ng/ml. PSA decline of at least 50% at 12 wk was achieved in 22 (58%) patients, while median time to pain progression was 8.3 (95% confidence interval [CI] 4.1-12.6) mouth. Median overall survival was 11.6 (95% CI 8.8-14.3) mouth."	.
REF00096	PDC_00327	Pancreatic ductal adenocarcinoma	Athymic CD1Nu/Nu female mice bearing human A375Pbeta6 xenograft tumours.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	97.7 &plusmn; 2	%	.	.	.	.	Pancreatic ductal adenocarcinoma	Capan-1 cell	.	"SG3299 was between 2.8- and 13.2-fold more selective for v6-positive pancreatic cells lines compared with SG3511, confirming that the anti-proliferative activity of SG3299 is more selective for v6-positive pancreatic cancer cells (Table (Table14)."	Bi-weekly for 4 weeks	25 &micro;g/kg	Tumor volume detection assay	"Again, SG3299 significantly reduced Capan-1 tumor growth achieving 97.7&plusmn;2% (P<0.0001) and 96.1&plusmn;3.4% (P<0.0001) reductions compared to PBS and SG3511, respectively."	SG3299 Treatment Reduces Pancreatic Tumor Growth by inducing DNA Damage and Apoptosis
REF00585	PDC_02066	Prostate cancer	Human plasma.	Identified from the Human Clinical Data	High Expreesion	Relative intensity	5%	%	.	.	.	.	.	.	.	.	60 min	1 &mu;g/ml	.	"GOXG2 was the least stable, followed by GOXG1, while GN4OXG was the most stable."	"We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA)."
REF00585	PDC_02065	Prostate cancer	Human plasma.	Identified from the Human Clinical Data	High Expreesion	Relative intensity	30%	%	.	.	.	.	.	.	.	.	60 min	1 &mu;g/ml	.	"GOXG2 was the least stable, followed by GOXG1, while GN4OXG was the most stable."	"We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA)."
REF00585	PDC_02067	Prostate cancer	Human plasma.	Identified from the Human Clinical Data	High Expreesion	Relative intensity	75%	%	.	.	.	.	.	.	.	.	60 min	1 &mu;g/ml	.	"GOXG2 was the least stable, followed by GOXG1, while GN4OXG was the most stable."	"We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA)."
REF00099	PDC_00029	Prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall detection rates	38.50%	%	.	.	.	"Patients with biochemical relapse and negative conventional (MRI, MRS, CT scan and bone scintigraphy) imaging."	.	.	.	.	"3 h, 24 h and 72 h"	185 MBq	<sup>177</sup>Lu-PSMA SPECT scan assay	"A total of 26 patients, with a mean age of 70 years (range: 46 to 89 years) were included in this study. The overall detection rates were 38.5% (10 out of 26 patients)."	.
REF00585	PDC_02066	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Relative intensity	0%	%	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	10 h	1 &mu;M	.	"This experiment showed that the more labile pro-drug was GOXG2, which was almost fully degraded in less than 10 hours while GN4OXG and GOXG1 showed similar, enhanced stability compared to GOXG2."	"We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA)."
REF00585	PDC_02065	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Relative intensity	10%	%	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	10 h	1 &mu;M	.	"This experiment showed that the more labile pro-drug was GOXG2, which was almost fully degraded in less than 10 hours while GN4OXG and GOXG1 showed similar, enhanced stability compared to GOXG2."	"We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA)."
REF00585	PDC_02067	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Relative intensity	12%	%	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	10 h	1 &mu;M	.	"This experiment showed that the more labile pro-drug was GOXG2, which was almost fully degraded in less than 10 hours while GN4OXG and GOXG1 showed similar, enhanced stability compared to GOXG2."	"We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA)."
REF00103	PDC_00027	Sinonasal neuroendocrine carcinomas	A 52-year-old man with SNC.	Identified from the Human Clinical Data	High Expreesion	Lymph node decrease rate	42.30%	%	.	.	.	.	.	.	.	.	.	&tilde;7.4 GBq [200 mCi]	.	"On follow-up for a second PRRT cycle, there was a complete symptomatic response. Follow-up scans showed a significant decrease in the size of the sinonasal mass (&tilde;1.9 0.8 cm vs. 7.0 4.6 5.0 cm at baseline), with a significant decrease in the size of the left cervical level II lymph node (1.5 1.1 cm vs. 2.2 1.3 cm at baseline) and complete resolution of the right hilar lymph node."	.
REF00027	PDC_00027	SSR positive lung neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Less progressive disease	p Values	.	.	.	.	Patients with somatostatin-expressing neuroendocrine tumors who underwent Lu-DOTATATE PRRT; with CRHE.	.	.	.	.	.	.	.	"Following PRRT, 76.5% of patients with CRHE experienced benefit (partial response + stable disease), whereas 23.4% experienced progressive disease. Patients with CRHE showed more stable disease (P = 0.048) and less progressive disease (P = 0.046) following PRRT compared with no CRHE."	.
REF00067	PDC_00150	Tumor	PC-3 xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	69.23%	%	.	.	.	.	.	.	.	.	38 days	0.625 mg/kg	.	"At the MTD dose, ER-472 treatment resulted in significant antitumor activity in all 3 models, but at 1/2 MTD no antitumor activity was observed in MIA PaCa-2 or BxPC-3 xenografts. In contrast, a much wider therapeutic window was observed for ER-472 in PC-3 xenografts: tumor regression and several tumor cures were observed at 1/2 MTD and significant antitumor activity was also recorded at the 1/4 MTD dose."	"Collectively, our data demonstrate that Cltx within ER-472 acts a cryptic peptide which is metabolized to peptides with C-terminal R-COOH in the tumor microenvironment. These peptides bind to tumor cell NRP1 to increase drug uptake, which consequently boosts the antitumor effect."
REF00067	PDC_00150	Tumor	PC-3 xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	100%	%	.	.	.	.	.	.	.	.	38 days	1.25 mg/kg	.	"At the MTD dose, ER-472 treatment resulted in significant antitumor activity in all 3 models, but at 1/2 MTD no antitumor activity was observed in MIA PaCa-2 or BxPC-3 xenografts. In contrast, a much wider therapeutic window was observed for ER-472 in PC-3 xenografts: tumor regression and several tumor cures were observed at 1/2 MTD and significant antitumor activity was also recorded at the 1/4 MTD dose."	"Collectively, our data demonstrate that Cltx within ER-472 acts a cryptic peptide which is metabolized to peptides with C-terminal R-COOH in the tumor microenvironment. These peptides bind to tumor cell NRP1 to increase drug uptake, which consequently boosts the antitumor effect."
REF00067	PDC_00150	Tumor	BxPC-3 xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	5.45%	%	.	.	.	.	.	.	.	.	23days	1.25 mg/kg	.	"At the MTD dose, ER-472 treatment resulted in significant antitumor activity in all 3 models, but at 1/2 MTD no antitumor activity was observed in MIA PaCa-2 or BxPC-3 xenografts. In contrast, a much wider therapeutic window was observed for ER-472 in PC-3 xenografts: tumor regression and several tumor cures were observed at 1/2 MTD and significant antitumor activity was also recorded at the 1/4 MTD dose."	"Collectively, our data demonstrate that Cltx within ER-472 acts a cryptic peptide which is metabolized to peptides with C-terminal R-COOH in the tumor microenvironment. These peptides bind to tumor cell NRP1 to increase drug uptake, which consequently boosts the antitumor effect."
REF00067	PDC_00150	Tumor	MIA PaCa-2 xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	36.70%	%	.	.	.	.	.	.	.	.	30 days	1.25 mg/kg	.	"At the MTD dose, ER-472 treatment resulted in significant antitumor activity in all 3 models, but at 1/2 MTD no antitumor activity was observed in MIA PaCa-2 or BxPC-3 xenografts. In contrast, a much wider therapeutic window was observed for ER-472 in PC-3 xenografts: tumor regression and several tumor cures were observed at 1/2 MTD and significant antitumor activity was also recorded at the 1/4 MTD dose."	"Collectively, our data demonstrate that Cltx within ER-472 acts a cryptic peptide which is metabolized to peptides with C-terminal R-COOH in the tumor microenvironment. These peptides bind to tumor cell NRP1 to increase drug uptake, which consequently boosts the antitumor effect."
REF00067	PDC_00150	Tumor	MIA PaCa-2 xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	100%	%	.	.	.	.	.	.	.	.	30 days	2.5 mg/kg	.	"At the MTD dose, ER-472 treatment resulted in significant antitumor activity in all 3 models, but at 1/2 MTD no antitumor activity was observed in MIA PaCa-2 or BxPC-3 xenografts. In contrast, a much wider therapeutic window was observed for ER-472 in PC-3 xenografts: tumor regression and several tumor cures were observed at 1/2 MTD and significant antitumor activity was also recorded at the 1/4 MTD dose."	"Collectively, our data demonstrate that Cltx within ER-472 acts a cryptic peptide which is metabolized to peptides with C-terminal R-COOH in the tumor microenvironment. These peptides bind to tumor cell NRP1 to increase drug uptake, which consequently boosts the antitumor effect."
REF00067	PDC_00150	Tumor	BxPC-3 xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	74.54%	%	.	.	.	.	.	.	.	.	23days	2.5 mg/kg	.	"At the MTD dose, ER-472 treatment resulted in significant antitumor activity in all 3 models, but at 1/2 MTD no antitumor activity was observed in MIA PaCa-2 or BxPC-3 xenografts. In contrast, a much wider therapeutic window was observed for ER-472 in PC-3 xenografts: tumor regression and several tumor cures were observed at 1/2 MTD and significant antitumor activity was also recorded at the 1/4 MTD dose."	"Collectively, our data demonstrate that Cltx within ER-472 acts a cryptic peptide which is metabolized to peptides with C-terminal R-COOH in the tumor microenvironment. These peptides bind to tumor cell NRP1 to increase drug uptake, which consequently boosts the antitumor effect."
REF00157	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	A 46-year-old man who had progressive metastatic testicular mixed germ cell tumor.	Identified from the Human Clinical Data	High Expreesion	&alpha;-fetoprotein increase rate	61.89%	%	.	.	.	.	.	.	.	.	1 month	7.5 GBq	.	"<sup>177</sup>Lu-PSMA 7.5 GBq was given to the patient (-fetoprotein: 38,669 ng/mL), and posttherapy imaging was performed 48 hours after the intravenous administration of <sup>177</sup>Lu-PSMA. Adequate uptakes were detected in metastatic lesions on whole-body posttherapy images (A, B) similar to pretreatment 68Ga-PSMA PET/CT. The patient well tolerated the treatment without any adverse effects. However, in follow-up at month 1, -fetoprotein level progressed to 62,600 ng/mL, and 68Ga-PSMA PET/CT was planned."	.
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	22 relapsed/refractory multiple myeloma.	Identified from the Human Clinical Data	High Expreesion	Anemia	32%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"The safety population included patients who received &ge;1 dose of melflufen, daratumumab, or dexamethasone (melflufen group) and 26 patients who received daratumumab monotherapy. In the safety population, &ge;1 TEAE was reported in 21 patients (96%) with melflufen, daratumumab, and dexamethasone and 22 patients (85%) with daratumumab. Overall, grade &ge;3 TEAE occurred in 18 patients (82%) with melflufen, daratumumab, and dexamethasone and 14 patients (54%) with daratumumab. The most common hematologic grade &ge;3 TEAE were neutropenia (melflufen group, 11 patients [50%]; daratumumab group, 3 patients [12%]), thrombocytopenia (melflufen group, 11 patients [50%]; daratumumab group, 2 patients [8%]), and anemia (melflufen group, 7 patients [32%]; daratumumab group, 5 patients [19%]). The most common non-hematologic grade &ge;3 TEAE were pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]) and femur fracture (melflufen group, 0 patients [0%]; daratumumab group, 2 patients [8%]); of these, 1 event (5%) of pneumonia in the melflufen group and 1 event (4%) of femur fracture in the daratumumab group were considered treatment-related TEAE by the investigator. Serious AE occurred in 6 patients (27%) with melflufen, daratumumab, and dexamethasone, and 12 patients (46%) with daratumumab. The most common serious AE (occurring in &ge;4 patients overall) were anemia (melflufen group, 2 patients [9%]; daratumumab group, 3 patients [12%]) and pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]). TEAE leading to treatment discontinuation occurred in 2 patients (9%) in the melflufen group (neutropenia and thrombocytopenia, N=1 each) and 4 patients (15%) in the daratumumab group (anemia, disease progression, hypercalcemia, and renal failure, N=1 each). Overall, 5 patients died on study before the crossover: 2 patients who received melflufen, daratumumab, and dexamethasone (1 due to disease progression and 1 due to unknown reasons, both >30 days after the last dose of study treatment) and 3 patients who received daratumumab (1 due to disease progression and 1 due to unknown reasons, both &le;30 days after the last dose of study treatment and 1 due to an AE [COVID-19 pneumonia], >30 days after the last dose of study treatment). In addition, one patient who crossed over to receive melflufen, daratumumab, and dexamethasone after progression on daratumumab died."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	22 relapsed/refractory multiple myeloma.	Identified from the Human Clinical Data	High Expreesion	Neutropenia	50%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"The safety population included patients who received &ge;1 dose of melflufen, daratumumab, or dexamethasone (melflufen group) and 26 patients who received daratumumab monotherapy. In the safety population, &ge;1 TEAE was reported in 21 patients (96%) with melflufen, daratumumab, and dexamethasone and 22 patients (85%) with daratumumab. Overall, grade &ge;3 TEAE occurred in 18 patients (82%) with melflufen, daratumumab, and dexamethasone and 14 patients (54%) with daratumumab. The most common hematologic grade &ge;3 TEAE were neutropenia (melflufen group, 11 patients [50%]; daratumumab group, 3 patients [12%]), thrombocytopenia (melflufen group, 11 patients [50%]; daratumumab group, 2 patients [8%]), and anemia (melflufen group, 7 patients [32%]; daratumumab group, 5 patients [19%]). The most common non-hematologic grade &ge;3 TEAE were pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]) and femur fracture (melflufen group, 0 patients [0%]; daratumumab group, 2 patients [8%]); of these, 1 event (5%) of pneumonia in the melflufen group and 1 event (4%) of femur fracture in the daratumumab group were considered treatment-related TEAE by the investigator. Serious AE occurred in 6 patients (27%) with melflufen, daratumumab, and dexamethasone, and 12 patients (46%) with daratumumab. The most common serious AE (occurring in &ge;4 patients overall) were anemia (melflufen group, 2 patients [9%]; daratumumab group, 3 patients [12%]) and pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]). TEAE leading to treatment discontinuation occurred in 2 patients (9%) in the melflufen group (neutropenia and thrombocytopenia, N=1 each) and 4 patients (15%) in the daratumumab group (anemia, disease progression, hypercalcemia, and renal failure, N=1 each). Overall, 5 patients died on study before the crossover: 2 patients who received melflufen, daratumumab, and dexamethasone (1 due to disease progression and 1 due to unknown reasons, both >30 days after the last dose of study treatment) and 3 patients who received daratumumab (1 due to disease progression and 1 due to unknown reasons, both &le;30 days after the last dose of study treatment and 1 due to an AE [COVID-19 pneumonia], >30 days after the last dose of study treatment). In addition, one patient who crossed over to receive melflufen, daratumumab, and dexamethasone after progression on daratumumab died."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	22 relapsed/refractory multiple myeloma.	Identified from the Human Clinical Data	High Expreesion	Neutrophil count decrease	9%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"The safety population included patients who received &ge;1 dose of melflufen, daratumumab, or dexamethasone (melflufen group) and 26 patients who received daratumumab monotherapy. In the safety population, &ge;1 TEAE was reported in 21 patients (96%) with melflufen, daratumumab, and dexamethasone and 22 patients (85%) with daratumumab. Overall, grade &ge;3 TEAE occurred in 18 patients (82%) with melflufen, daratumumab, and dexamethasone and 14 patients (54%) with daratumumab. The most common hematologic grade &ge;3 TEAE were neutropenia (melflufen group, 11 patients [50%]; daratumumab group, 3 patients [12%]), thrombocytopenia (melflufen group, 11 patients [50%]; daratumumab group, 2 patients [8%]), and anemia (melflufen group, 7 patients [32%]; daratumumab group, 5 patients [19%]). The most common non-hematologic grade &ge;3 TEAE were pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]) and femur fracture (melflufen group, 0 patients [0%]; daratumumab group, 2 patients [8%]); of these, 1 event (5%) of pneumonia in the melflufen group and 1 event (4%) of femur fracture in the daratumumab group were considered treatment-related TEAE by the investigator. Serious AE occurred in 6 patients (27%) with melflufen, daratumumab, and dexamethasone, and 12 patients (46%) with daratumumab. The most common serious AE (occurring in &ge;4 patients overall) were anemia (melflufen group, 2 patients [9%]; daratumumab group, 3 patients [12%]) and pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]). TEAE leading to treatment discontinuation occurred in 2 patients (9%) in the melflufen group (neutropenia and thrombocytopenia, N=1 each) and 4 patients (15%) in the daratumumab group (anemia, disease progression, hypercalcemia, and renal failure, N=1 each). Overall, 5 patients died on study before the crossover: 2 patients who received melflufen, daratumumab, and dexamethasone (1 due to disease progression and 1 due to unknown reasons, both >30 days after the last dose of study treatment) and 3 patients who received daratumumab (1 due to disease progression and 1 due to unknown reasons, both &le;30 days after the last dose of study treatment and 1 due to an AE [COVID-19 pneumonia], >30 days after the last dose of study treatment). In addition, one patient who crossed over to receive melflufen, daratumumab, and dexamethasone after progression on daratumumab died."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	22 relapsed/refractory multiple myeloma.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	50%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"The safety population included patients who received &ge;1 dose of melflufen, daratumumab, or dexamethasone (melflufen group) and 26 patients who received daratumumab monotherapy. In the safety population, &ge;1 TEAE was reported in 21 patients (96%) with melflufen, daratumumab, and dexamethasone and 22 patients (85%) with daratumumab. Overall, grade &ge;3 TEAE occurred in 18 patients (82%) with melflufen, daratumumab, and dexamethasone and 14 patients (54%) with daratumumab. The most common hematologic grade &ge;3 TEAE were neutropenia (melflufen group, 11 patients [50%]; daratumumab group, 3 patients [12%]), thrombocytopenia (melflufen group, 11 patients [50%]; daratumumab group, 2 patients [8%]), and anemia (melflufen group, 7 patients [32%]; daratumumab group, 5 patients [19%]). The most common non-hematologic grade &ge;3 TEAE were pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]) and femur fracture (melflufen group, 0 patients [0%]; daratumumab group, 2 patients [8%]); of these, 1 event (5%) of pneumonia in the melflufen group and 1 event (4%) of femur fracture in the daratumumab group were considered treatment-related TEAE by the investigator. Serious AE occurred in 6 patients (27%) with melflufen, daratumumab, and dexamethasone, and 12 patients (46%) with daratumumab. The most common serious AE (occurring in &ge;4 patients overall) were anemia (melflufen group, 2 patients [9%]; daratumumab group, 3 patients [12%]) and pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]). TEAE leading to treatment discontinuation occurred in 2 patients (9%) in the melflufen group (neutropenia and thrombocytopenia, N=1 each) and 4 patients (15%) in the daratumumab group (anemia, disease progression, hypercalcemia, and renal failure, N=1 each). Overall, 5 patients died on study before the crossover: 2 patients who received melflufen, daratumumab, and dexamethasone (1 due to disease progression and 1 due to unknown reasons, both >30 days after the last dose of study treatment) and 3 patients who received daratumumab (1 due to disease progression and 1 due to unknown reasons, both &le;30 days after the last dose of study treatment and 1 due to an AE [COVID-19 pneumonia], >30 days after the last dose of study treatment). In addition, one patient who crossed over to receive melflufen, daratumumab, and dexamethasone after progression on daratumumab died."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00096	PDC_00327	Pancreatic ductal adenocarcinoma	Athymic CD1Nu/Nu female mice bearing human Capan-1 xenograft tumours.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	84%	%	.	.	.	.	Pancreatic ductal adenocarcinoma	Capan-1 cell	.	"SG3299 was between 2.8- and 13.2-fold more selective for v6-positive pancreatic cells lines compared with SG3511, confirming that the anti-proliferative activity of SG3299 is more selective for v6-positive pancreatic cancer cells (Table(Table13)."	35 days	10 &micro;g/kg	Tumor volume detection assay	"Capan-1 xenografts responded in a similar manner to A375P6 xenografts upon 10 ug/kg tri-weekly treatment, with significant growth inhibition with SG3511 and SG3299 (P<0.0001). Again, SG3299 inhibited tumor growth significantly more than SG3511 (P<0.0001)."	SG3299 Treatment Reduces Pancreatic Tumor Growth by inducing DNA Damage and Apoptosis
REF00096	PDC_00327	Pancreatic ductal adenocarcinoma	Athymic CD1Nu/Nu female mice bearing human A375Pbeta6 xenograft tumours.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	79 &plusmn; 7%	%	.	.	.	.	Amelanotic melanoma	A375P-beta6 cell	.	"SG3299 was between 2.8- and 13.2-fold more selective for v6-positive pancreatic cells lines compared with SG3511, confirming that the anti-proliferative activity of SG3299 is more selective for v6-positive pancreatic cancer cells (Table(Table12)."	28 days	10 &micro;g/kg	Tumor volume detection assay	"In contrast, both SG3299 and SG3511 reduced A375P6 tumor growth compared with PBS treatment (79&plusmn;7% and 56.9&plusmn;16.2% respectively, P<0.0001) and SG3299 reduced growth by 2.3-fold more than SG3511 (P<0.0001)."	SG3299 Treatment Reduces Pancreatic Tumor Growth by inducing DNA Damage and Apoptosis
REF00096	PDC_00327	Pancreatic ductal adenocarcinoma	Athymic CD1Nu/Nu female mice bearing human A375Ppuro xenograft tumours.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	53.9 &plusmn; 23.7%	%	.	.	.	.	Amelanotic melanoma	A375P-puro cell	.	"SG3299 was between 2.8- and 13.2-fold more selective for v6-positive pancreatic cells lines compared with SG3511, confirming that the anti-proliferative activity of SG3299 is more selective for v6-positive pancreatic cancer cells (Table(Table11)."	28 days	10 &micro;g/kg	Tumor volume detection assay	"Tumors treated with SG3511 and SG3299 exhibited significant reductions in size (P<0.0001, 53.9&plusmn;23.7% and 34.8&plusmn;4.6% after 21 days respectively) but there was no significant difference in the effect of either treatment (P=0.24, after 30 days). "	SG3299 Treatment Reduces Pancreatic Tumor Growth by inducing DNA Damage and Apoptosis
REF00096	PDC_00327	Pancreatic ductal adenocarcinoma	Athymic CD1Nu/Nu female mice bearing human A375Pbeta6 xenograft tumours.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	76%	%	.	.	.	.	Pancreatic ductal adenocarcinoma	Panc 04.03 PS1 cell	.	"SG3299 was between 2.8- and 13.2-fold more selective for v6-positive pancreatic cells lines compared with SG3511, confirming that the anti-proliferative activity of SG3299 is more selective for v6-positive pancreatic cancer cells (Table(Table15)."	28 days	20 &micro;g/kg	Tumor volume detection assay	SG3299 significantly reduced Panc0403/PS1 xenograft tumor growth by 75.8&plusmn;6% (P<0.001) compared with PBS treatment and by 60.4&plusmn;9.8% (P<0.05) compared with SG3511 therapy.	SG3299 Treatment Reduces Pancreatic Tumor Growth by inducing DNA Damage and Apoptosis
REF00242; REF00039	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	57.00%	%	ACTRN12615000912583	.	Phase 2	"Between Aug 26, 2015, and Dec 8, 2016, 43 men were screened to identify 30 patients eligible for treatment. 26 (87%) had received at least one line of previous chemotherapy (80% docetaxel and 47% cabazitaxel) and 25 (83%) received prior abiraterone acetate, enzalutamide, or both."	.	.	41.1 &plusmn; 9.3 h	.	Every 6 weeks for up to six doses	7.4 GBq	.	"The authors reported that 57% of patients enrolled in the study had PSA reductions of greater than 50%, and significant improvements in quality of life were reported, which rapidly manifested after initiation of the therapy."	"After binding to the PSMA receptor, [<sup>177</sup>Lu]Lu-PSMA-617 is internalized into the PSMA positive cells, resulting in a long retention within these cells; the high energy electrons emitted during the decay can selectively induce tissue and DNA damage, leading to cell death."
REF00112	PDC_00003	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Inhibitory effect	82.84 &plusmn; 2.22%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	.	.	Wound healing and transwell assays	"The tumor invasion ability was also inhibited under the action of Pep and the PDC. Pep and PDC treatment resulted in a strong inhibition of invasion ability of SMCC-7721 cells with rates of 79.93 &plusmn; 3.86% and 82.84 &plusmn; 2.22%, respectively. These results were used to guide follow-up in vivo studies."	"Meanwhile, the thiol groups on Pep were used to covalently link it with a doxorubicin derivative (DOX-SH) and form PDC to kill tumors and inhibit tumor metastasis. Two doxorubicin molecules were linked to one Pep, and the drug loading was as high as 50.17%. The functional PDC molecule was synthesized from DOX-SH and 2,2-dipyridyl disulfide activated peptide (Pep-S-S-Py), and the molecular weight is 2565.98. CSNs were prepared for the effective codelivery of MMPI Pep and DOX to the tumor site. The MPL shell displayed a negative surface charge for prolonged blood circulation, and the PDC core was able to aggregate in the tumor matrix and adhere to the cell membrane. PDC aggregation could constantly release the MMPI peptide and DOX via low concentration and long-term glutathione-mediated reduction conditions in the tumor matrix. DOX can effectively enter the tumor cell and kill them. Meanwhile, MMPI peptide adherence to the cell membrane was able to selectively inhibit the activity of the MMP2 and achieve the effect of inhibiting tumor metastasis. Our study suggests that CSNs are of great potential for treating metastatic tumors."
REF00282	PDC_00341	Triple-negative breast cancer	4T1 tumor-bearing mice.	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	74% (Day 14)	%	.	.	.	.	Mammary carcinoma	4T1 cell	.	Further confocal imaging study confirmed that SN38-HKD/RGDR was more efficiently transported into both 4T1 cells and MVECs within 2 h compared with SN38-HKD.	"4-injection regimen (on day 0, 2, 4, and 6)"	10 mg/kg	Tumor volume detection assay	"SN38-HKD/RGDR slowed the 4T1 tumor growth by 74%, while irinotecan and SN38-HKD only showed 28% and 43% tumor growth inhibition, respectively, which was further confirmed by its capability in reducing tumor burden. "	"N38-HKD/RGDR increases infiltration, activity, and viability of CD8+ T cells, and thus inhibits the growth of primary tumors and pulmonary metastasis. This study highlights the synergistic modulation of cancerous cells and TECs with integrin-targeting PDC filaments as a promising strategy for TNBC chemoimmunotherapy."
REF00282	PDC_00341	Triple-negative breast cancer	EMT6 tumor-bearing mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	75% (Day 18)	%	.	.	.	.	Mammary gland malignant neoplasms	EMT6 cell	.	.	"4-injection regimen (on day 0, 2, 4, and 6)"	10 mg/kg	Tumor volume detection assay	"SN38-HKD/RGDR slowed the 4T1 tumor growth by 74%, while irinotecan and SN38-HKD only showed 28% and 43% tumor growth inhibition, respectively, which was further confirmed by its capability in reducing tumor burden. "	"N38-HKD/RGDR increases infiltration, activity, and viability of CD8+T cells, and thus inhibits the growth of primary tumors and pulmonary metastasis. This study highlights the synergistic modulation of cancerous cells and TECs with integrin-targeting PDC filaments as a promising strategy for TNBC chemoimmunotherapy."
REF00282	PDC_00340	Triple-negative breast cancer	4T1 tumor-bearing mice.	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	43% (Day 14)	%	.	.	.	.	Mammary carcinoma	4T1 cell	.	Further confocal imaging study confirmed that SN38-HKD/RGDR was more efficiently transported into both 4T1 cells and MVECs within 2 h compared with SN38-HKD.	"4-injection regimen (on day 0, 2, 4, and 6)"	10 mg/kg	Tumor volume detection assay	"SN38-HKD/RGDR slowed the 4T1 tumor growth by 74%, while irinotecan and SN38-HKD only showed 28% and 43% tumor growth inhibition, respectively, which was further confirmed by its capability in reducing tumor burden. "	"N38-HKD increases infiltration, activity, and viability of CD8+T cells, and thus inhibits the growth of primary tumors and pulmonary metastasis. This study highlights the synergistic modulation of cancerous cells and TECs with integrin-targeting PDC filaments as a promising strategy for TNBC chemoimmunotherapy."
REF00282	PDC_00340	Triple-negative breast cancer	EMT6 tumor-bearing mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	40% (Day 18)	%	.	.	.	.	Mammary gland malignant neoplasms	EMT6 cell	.	.	"4-injection regimen (on day 0, 2, 4, and 6)"	10 mg/kg	Tumor volume detection assay	"SN38-HKD/RGDR slowed the 4T1 tumor growth by 74%, while irinotecan and SN38-HKD only showed 28% and 43% tumor growth inhibition, respectively, which was further confirmed by its capability in reducing tumor burden. "	"N38-HKD increases infiltration, activity, and viability of CD8+T cells, and thus inhibits the growth of primary tumors and pulmonary metastasis. This study highlights the synergistic modulation of cancerous cells and TECs with integrin-targeting PDC filaments as a promising strategy for TNBC chemoimmunotherapy."
REF00222	PDC_00143	Non-small cell lung cancer	A549 cells mouse xenograft model.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	93.2% (Day 28)	%	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	.	Once a week for 4 weeks	20 mg/kg	Tumor volume detection assay	"Intraperitoneal administration of 20 mg/kg DTX-P7 (equivalent to DTX dose calculated as DTX) reduced tumor growth by 93.2% compared with control mice, whereas the tumor growth inhibition of DTX was only 35.9%. "	"Collecitvely, by force of active targeting delivery of DTX via membrane-bound Hsp90, DTX-P7 induces unfolded protein response and subsequent apoptosis by degrading Hsp90, meanwhile awakens and kills the dormant cancer stem cells."
REF00222	PDC_00143	Non-small cell lung cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	11.4 nM	nM	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"As exhibited in Figure 3A-D, the red fluorescence located in the cell nuclei of A549, HepG2, U87, and LO2 cells after treatment with free DOX for 4 h, indicating that free DOX could enter into both tumor and normal cells due to its poor selectivity to tumor cells. As for cells treated with the conjugates for 4 and 12 h (Figure 3 and Figure 4), the red fluorescence was mainly distributed in the cytoplasm of A549, HepG2, and U87 tumor cells but can barely be found in LO2 cells, indicating that the conjugates can selectively enter into tumor cells, and free DOX was not released from the conjugates. "	48 h	.	CCK-8 assay	"Intraperitoneal administration of 20 mg/kg DTX-P7 (equivalent to DTX dose calculated as DTX) reduced tumor growth by 93.2% compared with control mice, whereas the tumor growth inhibition of DTX was only 35.9%. "	"Collecitvely, by force of active targeting delivery of DTX via membrane-bound Hsp90, DTX-P7 induces unfolded protein response and subsequent apoptosis by degrading Hsp90, meanwhile awakens and kills the dormant cancer stem cells."
REF00222	PDC_00143	Non-small cell lung cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.62 nM	nM	.	.	.	.	Lung adenocarcinoma	H1975 cell	.	"As exhibited in Figure 3A-D, the red fluorescence located in the cell nuclei of A549, HepG2, U87, and LO2 cells after treatment with free DOX for 4 h, indicating that free DOX could enter into both tumor and normal cells due to its poor selectivity to tumor cells. As for cells treated with the conjugates for 4 and 12 h (Figure 3 and Figure 4), the red fluorescence was mainly distributed in the cytoplasm of A549, HepG2, and U87 tumor cells but can barely be found in LO2 cells, indicating that the conjugates can selectively enter into tumor cells, and free DOX was not released from the conjugates. "	48 h	.	CCK-8 assay	"Intraperitoneal administration of 20 mg/kg DTX-P7 (equivalent to DTX dose calculated as DTX) reduced tumor growth by 93.2% compared with control mice, whereas the tumor growth inhibition of DTX was only 35.9%. "	"Collecitvely, by force of active targeting delivery of DTX via membrane-bound Hsp90, DTX-P7 induces unfolded protein response and subsequent apoptosis by degrading Hsp90, meanwhile awakens and kills the dormant cancer stem cells."
REF00315	PDC_00049	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.70 &plusmn; 0.22 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U87 cell	.	"As exhibited in Figure 3A-D, the red fluorescence located in the cell nuclei of A549, HepG2, U87, and LO2 cells after treatment with free DOX for 4 h, indicating that free DOX could enter into both tumor and normal cells due to its poor selectivity to tumor cells. As for cells treated with the conjugates for 4 and 12 h (Figure 3 and Figure 4), the red fluorescence was mainly distributed in the cytoplasm of A549, HepG2, and U87 tumor cells but can barely be found in LO2 cells, indicating that the conjugates can selectively enter into tumor cells, and free DOX was not released from the conjugates. "	48 h	.	CCK-8 assay	"DT7-SS-DOX exhibited good in vitro antiproliferative activity against the three tumor cell lines, with IC50 values of 5.70 &plusmn; 0.22 &mu;M (U87), 7.01 &plusmn; 1.64 &mu;M (HepG2), and 20.61 &plusmn; 4.81 &mu;M (A549), respectively."	"Both conjugates exhibited targeted antiproliferative effects on TfR overexpressed tumor cells and little toxicity to TfR low-expressed normal cells compared with free DOX. Moreover, the DT7-SS-DOX conjugate possessed higher serum stability, more sustained reduction-triggered drug release characteristics, and stronger in vitro antiproliferative activity as compared to LT7-SS-DOX."
REF00315	PDC_00049	Hepatoblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.01 &plusmn; 1.64 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	"As exhibited in Figure 3A-D, the red fluorescence located in the cell nuclei of A549, HepG2, U87, and LO2 cells after treatment with free DOX for 4 h, indicating that free DOX could enter into both tumor and normal cells due to its poor selectivity to tumor cells. As for cells treated with the conjugates for 4 and 12 h (Figure 3 and Figure 4), the red fluorescence was mainly distributed in the cytoplasm of A549, HepG2, and U87 tumor cells but can barely be found in LO2 cells, indicating that the conjugates can selectively enter into tumor cells, and free DOX was not released from the conjugates. "	48 h	.	CCK-8 assay	"DT7-SS-DOX exhibited good in vitro antiproliferative activity against the three tumor cell lines, with IC50 values of 5.70 &plusmn; 0.22 &mu;M (U87), 7.01 &plusmn; 1.64 &mu;M (HepG2), and 20.61 &plusmn; 4.81 &mu;M (A549), respectively."	"Both conjugates exhibited targeted antiproliferative effects on TfR overexpressed tumor cells and little toxicity to TfR low-expressed normal cells compared with free DOX. Moreover, the DT7-SS-DOX conjugate possessed higher serum stability, more sustained reduction-triggered drug release characteristics, and stronger in vitro antiproliferative activity as compared to LT7-SS-DOX."
REF00315	PDC_00049	Lung adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	20.61 &plusmn; 4.81 &micro;M	&micro;M	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"As exhibited in Figure 3A-D, the red fluorescence located in the cell nuclei of A549, HepG2, U87, and LO2 cells after treatment with free DOX for 4 h, indicating that free DOX could enter into both tumor and normal cells due to its poor selectivity to tumor cells. As for cells treated with the conjugates for 4 and 12 h (Figure 3 and Figure 4), the red fluorescence was mainly distributed in the cytoplasm of A549, HepG2, and U87 tumor cells but can barely be found in LO2 cells, indicating that the conjugates can selectively enter into tumor cells, and free DOX was not released from the conjugates. "	48 h	.	CCK-8 assay	"DT7-SS-DOX exhibited good in vitro antiproliferative activity against the three tumor cell lines, with IC50 values of 5.70 &plusmn; 0.22 &mu;M (U87), 7.01 &plusmn; 1.64 &mu;M (HepG2), and 20.61 &plusmn; 4.81 &mu;M (A549), respectively."	"Both conjugates exhibited targeted antiproliferative effects on TfR overexpressed tumor cells and little toxicity to TfR low-expressed normal cells compared with free DOX. Moreover, the DT7-SS-DOX conjugate possessed higher serum stability, more sustained reduction-triggered drug release characteristics, and stronger in vitro antiproliferative activity as compared to LT7-SS-DOX."
REF00315	PDC_00049	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Proliferation inhibitory activity	95.10%	%	.	.	.	.	Glioblastoma	U87 cell	.	"As exhibited in Figure 3A-D, the red fluorescence located in the cell nuclei of A549, HepG2, U87, and LO2 cells after treatment with free DOX for 4 h, indicating that free DOX could enter into both tumor and normal cells due to its poor selectivity to tumor cells. As for cells treated with the conjugates for 4 and 12 h (Figure 3 and Figure 4), the red fluorescence was mainly distributed in the cytoplasm of A549, HepG2, and U87 tumor cells but can barely be found in LO2 cells, indicating that the conjugates can selectively enter into tumor cells, and free DOX was not released from the conjugates. "	48 h	.	CCK-8 assay	"The proliferation inhibitory activity of LT7-SS-DOX was the weakest among the three drugs because the cell viabilities of U87, HepG2, and A549 cells after incubation with LT7-SS-DOX (equal DOX concentration of 20 &mu;M) for 48 h were 95.1%, 73.1%, and 83.2%, respectively. "	"Both conjugates exhibited targeted antiproliferative effects on TfR overexpressed tumor cells and little toxicity to TfR low-expressed normal cells compared with free DOX. Moreover, the DT7-SS-DOX conjugate possessed higher serum stability, more sustained reduction-triggered drug release characteristics, and stronger in vitro antiproliferative activity as compared to LT7-SS-DOX."
REF00315	PDC_00050	Hepatoblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Proliferation inhibitory activity	73.10%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	"As exhibited in Figure 3A-D, the red fluorescence located in the cell nuclei of A549, HepG2, U87, and LO2 cells after treatment with free DOX for 4 h, indicating that free DOX could enter into both tumor and normal cells due to its poor selectivity to tumor cells. As for cells treated with the conjugates for 4 and 12 h (Figure 3 and Figure 4), the red fluorescence was mainly distributed in the cytoplasm of A549, HepG2, and U87 tumor cells but can barely be found in LO2 cells, indicating that the conjugates can selectively enter into tumor cells, and free DOX was not released from the conjugates. "	48 h	.	CCK-8 assay	"The proliferation inhibitory activity of LT7-SS-DOX was the weakest among the three drugs because the cell viabilities of U87, HepG2, and A549 cells after incubation with LT7-SS-DOX (equal DOX concentration of 20 &mu;M) for 48 h were 95.1%, 73.1%, and 83.2%, respectively. "	"Both conjugates exhibited targeted antiproliferative effects on TfR overexpressed tumor cells and little toxicity to TfR low-expressed normal cells compared with free DOX. Moreover, the DT7-SS-DOX conjugate possessed higher serum stability, more sustained reduction-triggered drug release characteristics, and stronger in vitro antiproliferative activity as compared to LT7-SS-DOX."
REF00315	PDC_00050	Lung adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Proliferation inhibitory activity	83.20%	%	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"As exhibited in Figure 3A-D, the red fluorescence located in the cell nuclei of A549, HepG2, U87, and LO2 cells after treatment with free DOX for 4 h, indicating that free DOX could enter into both tumor and normal cells due to its poor selectivity to tumor cells. As for cells treated with the conjugates for 4 and 12 h (Figure 3 and Figure 4), the red fluorescence was mainly distributed in the cytoplasm of A549, HepG2, and U87 tumor cells but can barely be found in LO2 cells, indicating that the conjugates can selectively enter into tumor cells, and free DOX was not released from the conjugates. "	48 h	.	CCK-8 assay	"The proliferation inhibitory activity of LT7-SS-DOX was the weakest among the three drugs because the cell viabilities of U87, HepG2, and A549 cells after incubation with LT7-SS-DOX (equal DOX concentration of 20 &mu;M) for 48 h were 95.1%, 73.1%, and 83.2%, respectively. "	"Both conjugates exhibited targeted antiproliferative effects on TfR overexpressed tumor cells and little toxicity to TfR low-expressed normal cells compared with free DOX. Moreover, the DT7-SS-DOX conjugate possessed higher serum stability, more sustained reduction-triggered drug release characteristics, and stronger in vitro antiproliferative activity as compared to LT7-SS-DOX."
REF00315	PDC_00050	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Proliferation inhibitory activity	41.00%	%	.	.	.	.	Glioblastoma	U87 cell	.	"As exhibited in Figure 3A-D, the red fluorescence located in the cell nuclei of A549, HepG2, U87, and LO2 cells after treatment with free DOX for 4 h, indicating that free DOX could enter into both tumor and normal cells due to its poor selectivity to tumor cells. As for cells treated with the conjugates for 4 and 12 h (Figure 3 and Figure 4), the red fluorescence was mainly distributed in the cytoplasm of A549, HepG2, and U87 tumor cells but can barely be found in LO2 cells, indicating that the conjugates can selectively enter into tumor cells, and free DOX was not released from the conjugates. "	48 h	.	CCK-8 assay	"Even at an equal DOX concentration of 40 &mu;M, the cell viability of the three types of tumor cells after exposure to this conjugate for 48 h were 41.0%, 61.5%, and 67.2%, respectively."	"Both conjugates exhibited targeted antiproliferative effects on TfR overexpressed tumor cells and little toxicity to TfR low-expressed normal cells compared with free DOX. Moreover, the DT7-SS-DOX conjugate possessed higher serum stability, more sustained reduction-triggered drug release characteristics, and stronger in vitro antiproliferative activity as compared to LT7-SS-DOX."
REF00315	PDC_00050	Hepatoblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Proliferation inhibitory activity	61.50%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	"As exhibited in Figure 3A-D, the red fluorescence located in the cell nuclei of A549, HepG2, U87, and LO2 cells after treatment with free DOX for 4 h, indicating that free DOX could enter into both tumor and normal cells due to its poor selectivity to tumor cells. As for cells treated with the conjugates for 4 and 12 h (Figure 3 and Figure 4), the red fluorescence was mainly distributed in the cytoplasm of A549, HepG2, and U87 tumor cells but can barely be found in LO2 cells, indicating that the conjugates can selectively enter into tumor cells, and free DOX was not released from the conjugates. "	48 h	.	CCK-8 assay	"Even at an equal DOX concentration of 40 &mu;M, the cell viability of the three types of tumor cells after exposure to this conjugate for 48 h were 41.0%, 61.5%, and 67.2%, respectively."	"Both conjugates exhibited targeted antiproliferative effects on TfR overexpressed tumor cells and little toxicity to TfR low-expressed normal cells compared with free DOX. Moreover, the DT7-SS-DOX conjugate possessed higher serum stability, more sustained reduction-triggered drug release characteristics, and stronger in vitro antiproliferative activity as compared to LT7-SS-DOX."
REF00315	PDC_00050	Lung adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Proliferation inhibitory activity	67.20%	%	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"As exhibited in Figure 3A-D, the red fluorescence located in the cell nuclei of A549, HepG2, U87, and LO2 cells after treatment with free DOX for 4 h, indicating that free DOX could enter into both tumor and normal cells due to its poor selectivity to tumor cells. As for cells treated with the conjugates for 4 and 12 h (Figure 3 and Figure 4), the red fluorescence was mainly distributed in the cytoplasm of A549, HepG2, and U87 tumor cells but can barely be found in LO2 cells, indicating that the conjugates can selectively enter into tumor cells, and free DOX was not released from the conjugates. "	48 h	.	CCK-8 assay	"Even at an equal DOX concentration of 40 &mu;M, the cell viability of the three types of tumor cells after exposure to this conjugate for 48 h were 41.0%, 61.5%, and 67.2%, respectively."	"Both conjugates exhibited targeted antiproliferative effects on TfR overexpressed tumor cells and little toxicity to TfR low-expressed normal cells compared with free DOX. Moreover, the DT7-SS-DOX conjugate possessed higher serum stability, more sustained reduction-triggered drug release characteristics, and stronger in vitro antiproliferative activity as compared to LT7-SS-DOX."
REF00096	PDC_00329	Pancreatic ductal adenocarcinoma	Athymic CD1Nu/Nu female mice bearing human A375Ppuro xenograft tumours.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	34.8 &plusmn; 4.6% (Day 28)	%	.	.	.	.	Amelanotic melanoma	A375P-puro cell	.	"SG3299 was between 2.8- and 13.2-fold more selective for v6-positive pancreatic cells lines compared with SG3511, confirming that the anti-proliferative activity of SG3299 is more selective for v6-positive pancreatic cancer cells (Table(Table16)."	T hrice weekly for 4 consecutive weeks	10 &micro;g/kg	Tumor volume detection assay	"Tumors treated with SG3511 and SG3299 exhibited significant reductions in size (P<0.0001, 53.9&plusmn;23.7% and 34.8&plusmn;4.6% after 21 days respectively) but there was no significant difference in the effect of either treatment (P=0.24, after 30 days)."	"Non-targeting SG3511 also produced a significant increase in apoptosis and DNA damage (P<0.05) again, probably as a result of the inherent lipophilicity of tesirine, but there was no significant change in tumor cell number, as measured by tumour cell area, CK-expression and confirmed with E-cadherin expression."
REF00096	PDC_00329	Pancreatic ductal adenocarcinoma	Athymic CD1Nu/Nu female mice bearing human A375Pbeta6 xenograft tumours.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	56.9 &plusmn; 16.2% (Day 28)	%	.	.	.	.	Amelanotic melanoma	A375P-beta6 cell	.	"SG3299 was between 2.8- and 13.2-fold more selective for v6-positive pancreatic cells lines compared with SG3511, confirming that the anti-proliferative activity of SG3299 is more selective for v6-positive pancreatic cancer cells (Table(Table17)."	T hrice weekly for 4 consecutive weeks	10 &micro;g/kg	Tumor volume detection assay	"In contrast, both SG3299 and SG3511 reduced A375P6 tumor growth compared with PBS treatment (79&plusmn;7% and 56.9&plusmn;16.2% respectively, P<0.0001) and SG3299 reduced growth by 2.3-fold more than SG3511 (P<0.0001)."	"Non-targeting SG3511 also produced a significant increase in apoptosis and DNA damage (P<0.05) again, probably as a result of the inherent lipophilicity of tesirine, but there was no significant change in tumor cell number, as measured by tumour cell area, CK-expression and confirmed with E-cadherin expression."
REF00096	PDC_00329	Pancreatic ductal adenocarcinoma	Athymic CD1Nu/Nu female mice bearing human Capan-1 xenograft tumours.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	75% (Day 35)	%	.	.	.	.	Pancreatic ductal adenocarcinoma	Capan-1 cell	.	"SG3299 was between 2.8- and 13.2-fold more selective for v6-positive pancreatic cells lines compared with SG3511, confirming that the anti-proliferative activity of SG3299 is more selective for v6-positive pancreatic cancer cells (Table(Table18)."	T hrice weekly for 5 consecutive weeks	10 &micro;g/kg	Tumor volume detection assay	"Capan-1 xenografts responded in a similar manner to A375P6 xenografts upon 10 ug/kg tri-weekly treatment, with significant growth inhibition with SG3511 and SG3299 (P<0.0001). Again, SG3299 inhibited tumor growth significantly more than SG3511 (P<0.0001)."	"Non-targeting SG3511 also produced a significant increase in apoptosis and DNA damage (P<0.05) again, probably as a result of the inherent lipophilicity of tesirine, but there was no significant change in tumor cell number, as measured by tumour cell area, CK-expression and confirmed with E-cadherin expression."
REF00096	PDC_00329	Pancreatic ductal adenocarcinoma	Athymic CD1Nu/Nu female mice bearing human A375Pbeta6 xenograft tumours.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	96.1 &plusmn; 3.4% (Day 28)	%	.	.	.	.	Pancreatic ductal adenocarcinoma	Capan-1 cell	.	"SG3299 was between 2.8- and 13.2-fold more selective for v6-positive pancreatic cells lines compared with SG3511, confirming that the anti-proliferative activity of SG3299 is more selective for v6-positive pancreatic cancer cells (Table(Table19)."	Bi-weekly for 4 weeks	25 &micro;g/kg	Tumor volume detection assay	"Again, SG3299 significantly reduced Capan-1 tumor growth achieving 97.7&plusmn;2% (P<0.0001) and 96.1&plusmn;3.4% (P<0.0001) reductions compared to PBS and SG3511, respectively."	"Non-targeting SG3511 also produced a significant increase in apoptosis and DNA damage (P<0.05) again, probably as a result of the inherent lipophilicity of tesirine, but there was no significant change in tumor cell number, as measured by tumour cell area, CK-expression and confirmed with E-cadherin expression."
REF00096	PDC_00329	Pancreatic ductal adenocarcinoma	Athymic CD1Nu/Nu female mice bearing human A375Pbeta6 xenograft tumours.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	34% (Day 28)	%	.	.	.	.	Pancreatic ductal adenocarcinoma	Panc 04.03 PS1 cell	.	"SG3299 was between 2.8- and 13.2-fold more selective for v6-positive pancreatic cells lines compared with SG3511, confirming that the anti-proliferative activity of SG3299 is more selective for v6-positive pancreatic cancer cells (Table(Table20)."	Bi-weekly for 4 weeks	20 &micro;g/kg	Tumor volume detection assay	SG3299 significantly reduced Panc0403/PS1 xenograft tumor growth by 75.8&plusmn;6% (P<0.001) compared with PBS treatment and by 60.4&plusmn;9.8% (P<0.05) compared with SG3511 therapy.	"Non-targeting SG3511 also produced a significant increase in apoptosis and DNA damage (P<0.05) again, probably as a result of the inherent lipophilicity of tesirine, but there was no significant change in tumor cell number, as measured by tumour cell area, CK-expression and confirmed with E-cadherin expression."
REF00089	PDC_00252	Tumor	Pan02 tumor model.	Obtained from the Model Organism Data	High Expreesion	Percentage of CD4 T cells	32%	%	.	.	.	.	Normal	CD4 T cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	30 min	25 &micro;M	Quantification of tumor-infiltrating immune cells assay	These findings support that aPD-L1 plus NLG-RGD NI efficiently elicits antitumor immunity by enhancing the activation and survival of immune effector cells and attenuating the accumulation immunosuppressive Treg cells.	"Significantly, this nanoinhibitor boosts the antitumor immune response of PD-L1 blockade by increasing immune effector cells and reducing immunosuppressive cells."
REF00089	PDC_00252	Tumor	Pan02 tumor model.	Obtained from the Model Organism Data	High Expreesion	Percentage of CD8 T cells	34%	%	.	.	.	.	Normal	CD8 T cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	30 min	25 &micro;M	Quantification of tumor-infiltrating immune cells assay	These findings support that aPD-L2 plus NLG-RGD NI efficiently elicits antitumor immunity by enhancing the activation and survival of immune effector cells and attenuating the accumulation immunosuppressive Treg cells.	"Significantly, this nanoinhibitor boosts the antitumor immune response of PD-L1 blockade by increasing immune effector cells and reducing immunosuppressive cells."
REF00089	PDC_00252	Tumor	Pan02 tumor model.	Obtained from the Model Organism Data	High Expreesion	Percentage of IFN-&gamma;-producing CD4 T cells	16%	%	.	.	.	.	Normal	IFN-gamma-producing CD4 T cell	.	"Increased intracellular accumulation of doxorubicin was observed with increasing incubation time for the ABD-RGDK/RPARPAR-DOXO conjugates. This kind of accumulation rate was notably inhibited when the cells were cultured in the presence of RGDK or RPARPAR (p < 0.01), indicating that the R/K-X-X-R/K motif in the fusion peptides could mediate the conjugates to penetrate into the A549 cell in a neuropilin-1dependent manner."	30 min	25 &micro;M	Quantification of tumor-infiltrating immune cells assay	These findings support that aPD-L3 plus NLG-RGD NI efficiently elicits antitumor immunity by enhancing the activation and survival of immune effector cells and attenuating the accumulation immunosuppressive Treg cells.	"Significantly, this nanoinhibitor boosts the antitumor immune response of PD-L1 blockade by increasing immune effector cells and reducing immunosuppressive cells."
REF00089	PDC_00252	Tumor	Pan02 tumor model.	Obtained from the Model Organism Data	High Expreesion	Percentage of IFN-&gamma;-producing CD8 T cells	40%	%	.	.	.	.	Normal	IFN-gamma-producing CD4 T cell	.	"Increased intracellular accumulation of doxorubicin was observed with increasing incubation time for the ABD-RGDK/RPARPAR-DOXO conjugates. This kind of accumulation rate was notably inhibited when the cells were cultured in the presence of RGDK or RPARPAR (p < 0.01), indicating that the R/K-X-X-R/K motif in the fusion peptides could mediate the conjugates to penetrate into the A549 cell in a neuropilin-1dependent manner."	30 min	25 &micro;M	Quantification of tumor-infiltrating immune cells assay	These findings support that aPD-L4 plus NLG-RGD NI efficiently elicits antitumor immunity by enhancing the activation and survival of immune effector cells and attenuating the accumulation immunosuppressive Treg cells.	"Significantly, this nanoinhibitor boosts the antitumor immune response of PD-L1 blockade by increasing immune effector cells and reducing immunosuppressive cells."
REF00089	PDC_00252	Tumor	Pan02 tumor model.	Obtained from the Model Organism Data	High Expreesion	Percentage of Treg cells	1%	%	.	.	.	.	Normal	Regulatory CD4+ T cell	.	"Increased intracellular accumulation of doxorubicin was observed with increasing incubation time for the ABD-RGDK/RPARPAR-DOXO conjugates. This kind of accumulation rate was notably inhibited when the cells were cultured in the presence of RGDK or RPARPAR (p < 0.01), indicating that the R/K-X-X-R/K motif in the fusion peptides could mediate the conjugates to penetrate into the A549 cell in a neuropilin-1dependent manner."	30 min	25 &micro;M	Quantification of tumor-infiltrating immune cells assay	These findings support that aPD-L5 plus NLG-RGD NI efficiently elicits antitumor immunity by enhancing the activation and survival of immune effector cells and attenuating the accumulation immunosuppressive Treg cells.	"Significantly, this nanoinhibitor boosts the antitumor immune response of PD-L1 blockade by increasing immune effector cells and reducing immunosuppressive cells."
REF00089	PDC_00252	Tumor	Pan02 tumor model.	Obtained from the Model Organism Data	High Expreesion	Percentage of NK cells	2%	%	.	.	.	.	Normal	Natural killer cell	.	"Increased intracellular accumulation of doxorubicin was observed with increasing incubation time for the ABD-RGDK/RPARPAR-DOXO conjugates. This kind of accumulation rate was notably inhibited when the cells were cultured in the presence of RGDK or RPARPAR (p < 0.01), indicating that the R/K-X-X-R/K motif in the fusion peptides could mediate the conjugates to penetrate into the A549 cell in a neuropilin-1dependent manner."	30 min	25 &micro;M	Quantification of tumor-infiltrating immune cells assay	These findings support that aPD-L6 plus NLG-RGD NI efficiently elicits antitumor immunity by enhancing the activation and survival of immune effector cells and attenuating the accumulation immunosuppressive Treg cells.	"Significantly, this nanoinhibitor boosts the antitumor immune response of PD-L1 blockade by increasing immune effector cells and reducing immunosuppressive cells."
REF00097	PDC_00239	Multiple myeloma	"Aged 18 years or older, had relapsed and refractory multiple myeloma, had received two or more previous lines of therapy (including lenalidomide and bortezomib)."	Identified from the Human Clinical Data	High Expreesion	Maximum tolerated dose	40 mg	mg	NCT01897714	The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.	Phase 1/2	.	.	.	.	.	"Intravenous (iv) infusion of 15 milligram (mg) melflufen on day 1 of each 21-day treatment cycle, in combination with 40 mg dexamet hasone (oral or iv) on days 1, 8 and 15 of each 21-day treatment cycle"	Melflufen 15 mg + Dexamethasone	.	"In phase 1, the established maximum tolerated dose was 40 mg of melflufen in combination with dexamethasone."	"The antineoplastic activity of melflufen is dependent upon the expression of aminopeptidases, like APN (also known as CD18), which cleave melflufen into melphalan and p-Fluorophenylalanine. Following aminopeptidase-dependent cleavage, the hydrophilic alkylating metabolite melphalan accumulates in myeloma cells. This enrichment of the cytotoxic payload has a substantial impact on the antimyeloma activity of melflufen."
REF00097	PDC_00239	Multiple myeloma	"Aged 18 years or older, had relapsed and refractory multiple myeloma, had received two or more previous lines of therapy (including lenalidomide and bortezomib)."	Identified from the Human Clinical Data	High Expreesion	Maximum tolerated dose	40 mg	mg	NCT01897714	The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.	Phase 1/2	.	.	.	.	.	"Iv infusion of 25 mg melflufen on day 1 of each 21-day treatment cycle, in combination with 40 mg dexamet hasone (oral or iv) on days 1, 8 and 15 of each 21-day treatment cycle"	Melflufen 25 mg + Dexamethasone	.	"In phase 1, the established maximum tolerated dose was 41 mg of melflufen in combination with dexamethasone."	"The antineoplastic activity of melflufen is dependent upon the expression of aminopeptidases, like APN (also known as CD18), which cleave melflufen into melphalan and p-Fluorophenylalanine. Following aminopeptidase-dependent cleavage, the hydrophilic alkylating metabolite melphalan accumulates in myeloma cells. This enrichment of the cytotoxic payload has a substantial impact on the antimyeloma activity of melflufen."
REF00097	PDC_00239	Multiple myeloma	"Aged 18 years or older, had relapsed and refractory multiple myeloma, had received two or more previous lines of therapy (including lenalidomide and bortezomib)."	Identified from the Human Clinical Data	High Expreesion	Maximum tolerated dose	40 mg	mg	NCT01897714	The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.	Phase 1/2	.	.	.	.	.	"Iv infusion of 40 mg melflufen on day 1 of each 21-day treatment cycle, in combination with 40 mg dexamet hasone (oral or iv) on days 1, 8 and 15 of each 21-day treatment cycle"	Melflufen 40 mg + Dexamethasone	.	"In phase 1, the established maximum tolerated dose was 42 mg of melflufen in combination with dexamethasone."	"The antineoplastic activity of melflufen is dependent upon the expression of aminopeptidases, like APN (also known as CD18), which cleave melflufen into melphalan and p-Fluorophenylalanine. Following aminopeptidase-dependent cleavage, the hydrophilic alkylating metabolite melphalan accumulates in myeloma cells. This enrichment of the cytotoxic payload has a substantial impact on the antimyeloma activity of melflufen."
REF00097	PDC_00239	Multiple myeloma	"Aged 18 years or older, had relapsed and refractory multiple myeloma, had received two or more previous lines of therapy (including lenalidomide and bortezomib)."	Identified from the Human Clinical Data	High Expreesion	Maximum tolerated dose	40 mg	mg	NCT01897714	The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.	Phase 1/2	.	.	.	.	.	"Iv infusion of 55 mg melflufen on day 1 of each 21-day treatment cycle, in combination with 40 mg dexamet hasone (oral or iv) on days 1, 8 and 15 of each 21-day treatment cycle"	Melflufen 55 mg + Dexamethasone	.	"In phase 1, the established maximum tolerated dose was 43 mg of melflufen in combination with dexamethasone."	"The antineoplastic activity of melflufen is dependent upon the expression of aminopeptidases, like APN (also known as CD18), which cleave melflufen into melphalan and p-Fluorophenylalanine. Following aminopeptidase-dependent cleavage, the hydrophilic alkylating metabolite melphalan accumulates in myeloma cells. This enrichment of the cytotoxic payload has a substantial impact on the antimyeloma activity of melflufen."
REF00097	PDC_00239	Multiple myeloma	"Aged 18 years or older, had relapsed and refractory multiple myeloma, had received two or more previous lines of therapy (including lenalidomide and bortezomib)."	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	31%	%	NCT01897714	The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.	Phase 1/2	.	.	.	.	.	"Iv infusion of 40 mg melflufen on day 1 of each 21-day or 28-day treatment cycles, in combination with 40 mg dexamet hasone (oral or iv) on days 1, 8 and 15 of each 21-day treatment cycles. for any patients on the 28-day treatment sc hedule, an additional dose of 40 mg dexamet hasone was administered on day 22 of each treatment cycle"	Melflufen 40 mg + Dexamethasone	.	"In phase 2, patients treated with combination therapy achieved an overall response rate of 31% (14 of 45 patients; 95% CI 18-47) and clinical benefit rate of 49% (22 of 45; 34-64)"	"The antineoplastic activity of melflufen is dependent upon the expression of aminopeptidases, like APN (also known as CD18), which cleave melflufen into melphalan and p-Fluorophenylalanine. Following aminopeptidase-dependent cleavage, the hydrophilic alkylating metabolite melphalan accumulates in myeloma cells. This enrichment of the cytotoxic payload has a substantial impact on the antimyeloma activity of melflufen."
REF00097	PDC_00239	Multiple myeloma	"Aged 18 years or older, had relapsed and refractory multiple myeloma, had received two or more previous lines of therapy (including lenalidomide and bortezomib)."	Identified from the Human Clinical Data	High Expreesion	Clinical benefit response rate (CBRR)	49%	%	NCT01897714	The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.	Phase 1/2	.	.	.	.	.	"Iv infusion of 40 mg melflufen on day 1 of each 21-day or 28-day treatment cycles, in combination with 40 mg dexamet hasone (oral or iv) on days 1, 8 and 15 of each 21-day treatment cycles. for any patients on the 28-day treatment sc hedule, an additional dose of 40 mg dexamet hasone was administered on day 22 of each treatment cycle"	Melflufen 40 mg + Dexamethasone	.	"In phase 2, patients treated with combination therapy achieved an overall response rate of 31% (14 of 45 patients; 95% CI 18-47) and clinical benefit rate of 49% (22 of 45; 34-64)"	"The antineoplastic activity of melflufen is dependent upon the expression of aminopeptidases, like APN (also known as CD18), which cleave melflufen into melphalan and p-Fluorophenylalanine. Following aminopeptidase-dependent cleavage, the hydrophilic alkylating metabolite melphalan accumulates in myeloma cells. This enrichment of the cytotoxic payload has a substantial impact on the antimyeloma activity of melflufen."
REF00097	PDC_00239	Multiple myeloma	"Aged 18 years or older, had relapsed and refractory multiple myeloma, had received two or more previous lines of therapy (including lenalidomide and bortezomib)."	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	8%	%	NCT01897714	The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.	Phase 1/2	.	.	.	.	.	Iv infusion of 40 mg melflufen on day 1 of each 28-day treatment cycle	Melflufen 40 mg (Single Agent)	.	"In the phase 2 single-agent cohort, the overall response rate was 8% (one of 13 patients; 02-360) and the clinical benefit rate was 23% (three of 13; 5-54)."	"The antineoplastic activity of melflufen is dependent upon the expression of aminopeptidases, like APN (also known as CD18), which cleave melflufen into melphalan and p-Fluorophenylalanine. Following aminopeptidase-dependent cleavage, the hydrophilic alkylating metabolite melphalan accumulates in myeloma cells. This enrichment of the cytotoxic payload has a substantial impact on the antimyeloma activity of melflufen."
REF00097	PDC_00239	Multiple myeloma	"Aged 18 years or older, had relapsed and refractory multiple myeloma, had received two or more previous lines of therapy (including lenalidomide and bortezomib)."	Identified from the Human Clinical Data	High Expreesion	Clinical benefit response rate (CBRR)	23%	%	NCT01897714	The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.	Phase 1/2	.	.	.	.	.	Iv infusion of 40 mg melflufen on day 1 of each 28-day treatment cycle	Melflufen 40 mg (Single Agent)	.	"In the phase 2 single-agent cohort, the overall response rate was 8% (one of 13 patients; 02-360) and the clinical benefit rate was 23% (three of 13; 5-54)."	"The antineoplastic activity of melflufen is dependent upon the expression of aminopeptidases, like APN (also known as CD18), which cleave melflufen into melphalan and p-Fluorophenylalanine. Following aminopeptidase-dependent cleavage, the hydrophilic alkylating metabolite melphalan accumulates in myeloma cells. This enrichment of the cytotoxic payload has a substantial impact on the antimyeloma activity of melflufen."
REF00098	PDC_00027	Metastatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Disease response rate (DRR)	27.58%	%	.	.	.	Patients with metastatic neuroendocrine tumours.	.	.	.	.	.	.	Response Evaluation Criteria in Solid Tumours	"The pooled effect in the RECIST group (13 studies) was 27.58% (95% confidence interval (CI) 21.03-35.27%) for the DRR and 79.14% (95% CI 75.83-82.1%) for the DCR. In the SWOG criteria group (7 studies), the pooled effect was 20.59% (95% CI 10.89-35.51%) for the DRR and 78.28% (95% CI 74.39-81.72%) for the DCR. "	.
REF00098	PDC_00027	Metastatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Disease control rate (DCR)	79.14%	%	.	.	.	Patients with metastatic neuroendocrine tumours.	.	.	.	.	.	.	Response Evaluation Criteria in Solid Tumours	"The pooled effect in the RECIST group (13 studies) was 27.58% (95% confidence interval (CI) 21.03-35.27%) for the DRR and 79.14% (95% CI 75.83-82.1%) for the DCR. In the SWOG criteria group (7 studies), the pooled effect was 20.59% (95% CI 10.89-35.51%) for the DRR and 78.28% (95% CI 74.39-81.72%) for the DCR. "	.
REF00098	PDC_00027	Metastatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Disease response rate (DRR)	20.59%	%	.	.	.	Patients with metastatic neuroendocrine tumours.	.	.	.	.	.	.	Southwest Oncology Group criteria	"The pooled effect in the RECIST group (13 studies) was 27.58% (95% confidence interval (CI) 21.03-35.27%) for the DRR and 79.14% (95% CI 75.83-82.1%) for the DCR. In the SWOG criteria group (7 studies), the pooled effect was 20.59% (95% CI 10.89-35.51%) for the DRR and 78.28% (95% CI 74.39-81.72%) for the DCR. "	.
REF00098	PDC_00027	Metastatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Disease control rate (DCR)	78.28%	%	.	.	.	Patients with metastatic neuroendocrine tumours.	.	.	.	.	.	.	Southwest Oncology Group criteria	"The pooled effect in the RECIST group (13 studies) was 27.58% (95% confidence interval (CI) 21.03-35.27%) for the DRR and 79.14% (95% CI 75.83-82.1%) for the DCR. In the SWOG criteria group (7 studies), the pooled effect was 20.59% (95% CI 10.89-35.51%) for the DRR and 78.28% (95% CI 74.39-81.72%) for the DCR. "	.
REF00093	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	24 months	months	.	.	.	"Patients with advanced Pan-neuroendocrine tumour, previously pretreated with one (67%) or several (33%) lines of chemotherapy."	.	.	.	.	1-10 cycles with 6- to 8-week intervals	7.4 GBq	.	"The median follow-up was 34 months, the median PFS was 24 months, and the median OS was 42 months from start of PRRT."	.
REF00093	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Overall survival (OS)	42 months	months	.	.	.	"Patients with advanced Pan-neuroendocrine tumour, previously pretreated with one (67%) or several (33%) lines of chemotherapy."	.	.	.	.	1-10 cycles with 6- to 8-week intervals	7.4 GBq	.	"The median follow-up was 34 months, the median PFS was 24 months, and the median OS was 42 months from start of PRRT."	.
REF00092	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	47 weeks	weeks	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6weeks	7.5 GBq	.	"There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258)."	.
REF00092	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	35.00%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6weeks	7.5 GBq	.	"There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258)."	.
REF00092	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Best PSA response	-40.20%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6weeks	7.5 GBq	.	"There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258)."	.
REF00092	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	11.3 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6weeks	7.5 GBq	.	"There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258)."	.
REF00092	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	9.5 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6weeks	7.5 GBq	.	"There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258)."	.
REF00092	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	47 weeks	weeks	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 8weeks	6.0 GBq	.	"There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258)."	.
REF00092	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	54.00%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 8weeks	6.0 GBq	.	"There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258)."	.
REF00092	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Best PSA response	-57.80%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 8weeks	6.0 GBq	.	"There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258)."	.
REF00092	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	12.7 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 8weeks	6.0 GBq	.	"There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258)."	.
REF00092	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	12.3 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 8weeks	6.0 GBq	.	"There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and - 40.2% vs. - 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258)."	.
REF00091	PDC_00057	Uveal melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	36.30%	%	.	.	.	.	Cutaneous melanoma	OCM-3 cell	.	OCM3 UM cell line expresses the LHRH receptor and LHRH rendering them susceptible to AEZS-108 uptake.	24 h	5 &micro;M	MTS assay	"In order to investigate whether AEZS-108 inhibits cell proliferation and its extent, OCM3 cells were treated either with 5 M AEZS-108 or equal amount of doxorubicin. MTS assay was performed after 24 and 48 hours of treatment. AEZS-108 and doxorubicin have been shown to reduce cell proliferation by 36.3% (p< 0.001) and 62.9% (p< 0.001) respectively after 24 hours, and by 84.7% (p< 0.001) and 89.7% (p< 0.001) respectively after 48 hours, (Figure 2)."	"Our results show that AEZS-108 upregulates the expression of MASPIN/SERPINB5 tumor suppressor gene, which is downregulated in normal uvea and UM specimens independently from the LHRH receptor-ligand interaction. AEZS-108 also substantially downregulates hypoxia-inducible factor 1 alpha (HIF1A) expression."
REF00091	PDC_00057	Uveal melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	84.70%	%	.	.	.	.	Cutaneous melanoma	OCM-3 cell	.	OCM3 UM cell line expresses the LHRH receptor and LHRH rendering them susceptible to AEZS-108 uptake. 	48 h	5 &micro;M	MTS assay	"In order to investigate whether AEZS-108 inhibits cell proliferation and its extent, OCM3 cells were treated either with 5 M AEZS-108 or equal amount of doxorubicin. MTS assay was performed after 24 and 48 hours of treatment. AEZS-108 and doxorubicin have been shown to reduce cell proliferation by 36.3% (p< 0.001) and 62.9% (p< 0.001) respectively after 24 hours, and by 84.7% (p< 0.001) and 89.7% (p< 0.001) respectively after 48 hours, (Figure 2)."	"Our results show that AEZS-108 upregulates the expression of MASPIN/SERPINB5 tumor suppressor gene, which is downregulated in normal uvea and UM specimens independently from the LHRH receptor-ligand interaction. AEZS-108 also substantially downregulates hypoxia-inducible factor 1 alpha (HIF1A) expression."
REF00090	PDC_00062	Breast cancer	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	15%	%	.	.	.	Adult patients with measurable recurrent brain metastases from breast cancer.	.	.	.	Preclinical studies using in situ mouse and rat brain penetrating models demonstrated increased ANG1005 brain uptake compared with paclitaxel and proved that ANG1005 is not a substrate to the P-glycoprotein (P-gp) efflux pump.	Every 3 weeks	600 mg/m<sup>2</sup>	.	"On the basis of the CNS tumor response assessment, performed by local investigators, there were nine (15%) evaluable patients with PR including five (8%) confirmed PR (to confirm PR, it was required that the response was sustained for &ge;4 weeks), and 32 (53%) evaluable patients with SD, resulting in an overall iORR of 15% and iCBR of 68%. "	"Because LRP1 is also expressed on tumor cells in both CNS and systemic metastases, ANG1005 gains entry via LRP1 mediated endocytosis, where paclitaxel is cleaved from the peptide backbone by lysosomal esterases."
REF00090	PDC_00062	Breast cancer	.	Identified from the Human Clinical Data	High Expreesion	Clinical benefit rate (CBR)	68%	%	.	.	.	Adult patients with measurable recurrent brain metastases from breast cancer.	.	.	.	Preclinical studies using in situ mouse and rat brain penetrating models demonstrated increased ANG1005 brain uptake compared with paclitaxel and proved that ANG1005 is not a substrate to the P-glycoprotein (P-gp) efflux pump.	Every 3 weeks	600 mg/m<sup>2</sup>	.	"On the basis of the CNS tumor response assessment, performed by local investigators, there were nine (15%) evaluable patients with PR including five (8%) confirmed PR (to confirm PR, it was required that the response was sustained for &ge;4 weeks), and 32 (53%) evaluable patients with SD, resulting in an overall iORR of 15% and iCBR of 68%. "	"Because LRP1 is also expressed on tumor cells in both CNS and systemic metastases, ANG1005 gains entry via LRP1 mediated endocytosis, where paclitaxel is cleaved from the peptide backbone by lysosomal esterases."
REF00090	PDC_00062	Breast cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	12.1 weeks	weeks	.	.	.	Adult patients with measurable recurrent brain metastases from breast cancer.	.	.	.	Preclinical studies using in situ mouse and rat brain penetrating models demonstrated increased ANG1005 brain uptake compared with paclitaxel and proved that ANG1005 is not a substrate to the P-glycoprotein (P-gp) efflux pump.	Every 3 weeks	600 mg/m<sup>2</sup>	.	Investigator assessments resulted in median intracranial PFS of 2.8 months and the 3-month intracranial PFS rate was 52%.	"Because LRP1 is also expressed on tumor cells in both CNS and systemic metastases, ANG1005 gains entry via LRP1 mediated endocytosis, where paclitaxel is cleaved from the peptide backbone by lysosomal esterases."
REF00090	PDC_00062	Breast cancer	.	Identified from the Human Clinical Data	High Expreesion	3-month progression-free survival rate	52.00%	%	.	.	.	Adult patients with measurable recurrent brain metastases from breast cancer.	.	.	.	Preclinical studies using in situ mouse and rat brain penetrating models demonstrated increased ANG1005 brain uptake compared with paclitaxel and proved that ANG1005 is not a substrate to the P-glycoprotein (P-gp) efflux pump.	Every 3 weeks	600 mg/m<sup>2</sup>	.	Investigator assessments resulted in median intracranial PFS of 2.8 months and the 3-month intracranial PFS rate was 52%.	"Because LRP1 is also expressed on tumor cells in both CNS and systemic metastases, ANG1005 gains entry via LRP1 mediated endocytosis, where paclitaxel is cleaved from the peptide backbone by lysosomal esterases."
REF00090	PDC_00062	Breast cancer	.	Identified from the Human Clinical Data	High Expreesion	6-month progression-free survival rate	18.70%	%	.	.	.	Adult patients with measurable recurrent brain metastases from breast cancer.	.	.	.	Preclinical studies using in situ mouse and rat brain penetrating models demonstrated increased ANG1005 brain uptake compared with paclitaxel and proved that ANG1005 is not a substrate to the P-glycoprotein (P-gp) efflux pump.	Every 3 weeks	600 mg/m<sup>2</sup>	.	Investigator assessments resulted in median intracranial PFS of 2.8 months and the 3-month intracranial PFS rate was 52%.	"Because LRP1 is also expressed on tumor cells in both CNS and systemic metastases, ANG1005 gains entry via LRP1 mediated endocytosis, where paclitaxel is cleaved from the peptide backbone by lysosomal esterases."
REF00090	PDC_00062	Breast cancer	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	29%	%	.	.	.	Patients with leptomeningeal carcinomatosis.	.	.	.	Preclinical studies using in situ mouse and rat brain penetrating models demonstrated increased ANG1005 brain uptake compared with paclitaxel and proved that ANG1005 is not a substrate to the P-glycoprotein (P-gp) efflux pump.	Every 3 weeks	600 mg/m<sup>2</sup>	.	Investigator determined ORR was 29% and the iCBR was 67%.	"Because LRP1 is also expressed on tumor cells in both CNS and systemic metastases, ANG1005 gains entry via LRP1 mediated endocytosis, where paclitaxel is cleaved from the peptide backbone by lysosomal esterases."
REF00090	PDC_00062	Breast cancer	.	Identified from the Human Clinical Data	High Expreesion	Clinical benefit rate (CBR)	67%	%	.	.	.	Patients with leptomeningeal carcinomatosis.	.	.	.	Preclinical studies using in situ mouse and rat brain penetrating models demonstrated increased ANG1005 brain uptake compared with paclitaxel and proved that ANG1005 is not a substrate to the P-glycoprotein (P-gp) efflux pump.	Every 3 weeks	600 mg/m<sup>2</sup>	.	Investigator determined ORR was 29% and the iCBR was 67%.	"Because LRP1 is also expressed on tumor cells in both CNS and systemic metastases, ANG1005 gains entry via LRP1 mediated endocytosis, where paclitaxel is cleaved from the peptide backbone by lysosomal esterases."
REF00090	PDC_00062	Breast cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	2.8 months	months	.	.	.	Patients with leptomeningeal carcinomatosis.	.	.	.	Preclinical studies using in situ mouse and rat brain penetrating models demonstrated increased ANG1005 brain uptake compared with paclitaxel and proved that ANG1005 is not a substrate to the P-glycoprotein (P-gp) efflux pump.	Every 3 weeks	600 mg/m<sup>2</sup>	.	The investigator determined intracranial median PFS was 2.8 months and the 3-month PFS rate was 54% (Table 3). Median duration of response was 18 weeks (7.3-26.3). 	"Because LRP1 is also expressed on tumor cells in both CNS and systemic metastases, ANG1005 gains entry via LRP1 mediated endocytosis, where paclitaxel is cleaved from the peptide backbone by lysosomal esterases."
REF00090	PDC_00062	Breast cancer	.	Identified from the Human Clinical Data	High Expreesion	3-month progression-free survival rate	54.00%	%	.	.	.	Patients with leptomeningeal carcinomatosis.	.	.	.	Preclinical studies using in situ mouse and rat brain penetrating models demonstrated increased ANG1005 brain uptake compared with paclitaxel and proved that ANG1005 is not a substrate to the P-glycoprotein (P-gp) efflux pump.	Every 3 weeks	600 mg/m<sup>2</sup>	.	The investigator determined intracranial median PFS was 2.8 months and the 3-month PFS rate was 54% (Table 3). Median duration of response was 18 weeks (7.3-26.3). 	"Because LRP1 is also expressed on tumor cells in both CNS and systemic metastases, ANG1005 gains entry via LRP1 mediated endocytosis, where paclitaxel is cleaved from the peptide backbone by lysosomal esterases."
REF00090	PDC_00062	Breast cancer	.	Identified from the Human Clinical Data	High Expreesion	Median duration of response	18 weeks	weeks	.	.	.	Patients with leptomeningeal carcinomatosis.	.	.	.	Preclinical studies using in situ mouse and rat brain penetrating models demonstrated increased ANG1005 brain uptake compared with paclitaxel and proved that ANG1005 is not a substrate to the P-glycoprotein (P-gp) efflux pump.	Every 3 weeks	600 mg/m<sup>2</sup>	.	The investigator determined intracranial median PFS was 2.8 months and the 3-month PFS rate was 54% (Table 3). Median duration of response was 18 weeks (7.3-26.3). 	"Because LRP1 is also expressed on tumor cells in both CNS and systemic metastases, ANG1005 gains entry via LRP1 mediated endocytosis, where paclitaxel is cleaved from the peptide backbone by lysosomal esterases."
REF00088	PDC_00347	Type 2 diabetes	db/db mice model.	Obtained from the Model Organism Data	High Expreesion	Body weigth change	10%	%	.	.	.	.	.	.	.	.	Every day; over 8 days	2.5 &micro;M	Body weigth change assay	"The mice treated with tesa and tesa-NPY (3) did not change significantly, whereas their littermates treated with [F7, P34]-NPY (2) or vehicle/untreated lost approximately 3% of their body weight (Figure 7A)."	"In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPAR&gamma; in NPY7R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo."
REF00088	PDC_00347	Type 2 diabetes	db/db mice model.	Obtained from the Model Organism Data	High Expreesion	HbA1C change	1.05%	%	.	.	.	.	.	.	.	.	Every day; over 8 days	2.5 &micro;M	.	"Whereas in the vehicle/untreated mice, the HbA1C values increased by approximately 2%, a graduated reduced increase was seen for [F7, P34]-NPY (2), peptide conjugate (3), and tesa (Figure 8A). Body temperature, which decreased to 35 C in the vehicle/untreated db/db controls, was normalized to 36 C in all of the treated mice including the mice treated with [F7, P34]-NPY (2) (Figure 8B). Treatment with tesa and tesa-NPY (3) led to normalization of the plasma concentration of ketone bodies and adiponectin, whereas [F7, P34]-NPY (2) and vehicle/untreated showed no effect (Figure 8C/E). Treatment had no major influence on the insulin and Mcp-1 levels (Figure 8D/G). The serum leptin concentration was reduced in the mice treated with tesa, whereas no reduction was detectable in all of the other treated mice (Figure 8F)."	"In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPAR&gamma; in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo."
REF00088	PDC_00347	Type 2 diabetes	db/db mice model.	Obtained from the Model Organism Data	High Expreesion	Ketone level	0.5 mM/L	mM/L	.	.	.	.	.	.	.	.	Every day; over 8 days	2.5 &micro;M	.	"Whereas in the vehicle/untreated mice, the HbA1C values increased by approximately 2%, a graduated reduced increase was seen for [F7, P34]-NPY (2), peptide conjugate (3), and tesa (Figure 8A). Body temperature, which decreased to 35 C in the vehicle/untreated db/db controls, was normalized to 36 C in all of the treated mice including the mice treated with [F7, P34]-NPY (2) (Figure 8B). Treatment with tesa and tesa-NPY (3) led to normalization of the plasma concentration of ketone bodies and adiponectin, whereas [F7, P34]-NPY (2) and vehicle/untreated showed no effect (Figure 8C/E). Treatment had no major influence on the insulin and Mcp-1 levels (Figure 8D/G). The serum leptin concentration was reduced in the mice treated with tesa, whereas no reduction was detectable in all of the other treated mice (Figure 8F)."	"In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPAR&gamma; in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo."
REF00088	PDC_00347	Type 2 diabetes	db/db mice model.	Obtained from the Model Organism Data	High Expreesion	Insulin level	2 ng/mL	ng/mL	.	.	.	.	.	.	.	.	Every day; over 8 days	2.5 &micro;M	.	"Whereas in the vehicle/untreated mice, the HbA1C values increased by approximately 2%, a graduated reduced increase was seen for [F7, P34]-NPY (2), peptide conjugate (3), and tesa (Figure 8A). Body temperature, which decreased to 35 C in the vehicle/untreated db/db controls, was normalized to 36 C in all of the treated mice including the mice treated with [F7, P34]-NPY (2) (Figure 8B). Treatment with tesa and tesa-NPY (3) led to normalization of the plasma concentration of ketone bodies and adiponectin, whereas [F7, P34]-NPY (2) and vehicle/untreated showed no effect (Figure 8C/E). Treatment had no major influence on the insulin and Mcp-1 levels (Figure 8D/G). The serum leptin concentration was reduced in the mice treated with tesa, whereas no reduction was detectable in all of the other treated mice (Figure 8F)."	"In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPAR&gamma; in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo."
REF00088	PDC_00347	Type 2 diabetes	db/db mice model.	Obtained from the Model Organism Data	High Expreesion	Mcp-1 level	305 pg/mL	pg/mL	.	.	.	.	.	.	.	.	Every day; over 8 days	2.5 &micro;M	.	"Whereas in the vehicle/untreated mice, the HbA1C values increased by approximately 2%, a graduated reduced increase was seen for [F7, P34]-NPY (2), peptide conjugate (3), and tesa (Figure 8A). Body temperature, which decreased to 35 C in the vehicle/untreated db/db controls, was normalized to 36 C in all of the treated mice including the mice treated with [F7, P34]-NPY (2) (Figure 8B). Treatment with tesa and tesa-NPY (3) led to normalization of the plasma concentration of ketone bodies and adiponectin, whereas [F7, P34]-NPY (2) and vehicle/untreated showed no effect (Figure 8C/E). Treatment had no major influence on the insulin and Mcp-1 levels (Figure 8D/G). The serum leptin concentration was reduced in the mice treated with tesa, whereas no reduction was detectable in all of the other treated mice (Figure 8F)."	"In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPAR&gamma; in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo."
REF00088	PDC_00347	Type 2 diabetes	db/db mice model.	Obtained from the Model Organism Data	High Expreesion	Leptin level	82 ng/mL	ng/mL	.	.	.	.	.	.	.	.	Every day; over 8 days	2.5 &micro;M	.	"Whereas in the vehicle/untreated mice, the HbA1C values increased by approximately 2%, a graduated reduced increase was seen for [F7, P34]-NPY (2), peptide conjugate (3), and tesa (Figure 8A). Body temperature, which decreased to 35 C in the vehicle/untreated db/db controls, was normalized to 36 C in all of the treated mice including the mice treated with [F7, P34]-NPY (2) (Figure 8B). Treatment with tesa and tesa-NPY (3) led to normalization of the plasma concentration of ketone bodies and adiponectin, whereas [F7, P34]-NPY (2) and vehicle/untreated showed no effect (Figure 8C/E). Treatment had no major influence on the insulin and Mcp-1 levels (Figure 8D/G). The serum leptin concentration was reduced in the mice treated with tesa, whereas no reduction was detectable in all of the other treated mice (Figure 8F)."	"In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPAR&gamma; in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo."
REF00088	PDC_00347	Type 2 diabetes	db/db mice model.	Obtained from the Model Organism Data	High Expreesion	Triglycerides level	0.9	.	.	.	.	.	.	.	.	.	Every day; over 8 days	2.5 &micro;M	.	"The influence of tesa, tesa-NPY (3), and [F7, P34]-NPY (2) on the plasma lipids was also analyzed (Figure 9). The vehicle/untreated db/db mice showed elevated levels of triglycerides and free fatty acids (FFA) compared to the lean C57BL/6N mice. Treatment with tesa and tesa-NPY (3) led to a normalization of the triglycerides, FFA, whereas [F7, P34]-NPY (2) and vehicle/untreated had no influence on the lipid metabolism (Figure 9A/B). The cholesterol levels were unchanged by any treatment as these levels were also comparable in the untreated db/db mice compared to the lean mice (Figure 9C)."	"In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPAR&gamma; in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo."
REF00088	PDC_00347	Type 2 diabetes	db/db mice model.	Obtained from the Model Organism Data	High Expreesion	Triglycerides level	0.65	.	.	.	.	.	.	.	.	.	Every day; over 8 days	2.5 &micro;M	.	"The influence of tesa, tesa-NPY (3), and [F7, P34]-NPY (2) on the plasma lipids was also analyzed (Figure 9). The vehicle/untreated db/db mice showed elevated levels of triglycerides and free fatty acids (FFA) compared to the lean C57BL/6N mice. Treatment with tesa and tesa-NPY (3) led to a normalization of the triglycerides, FFA, whereas [F7, P34]-NPY (2) and vehicle/untreated had no influence on the lipid metabolism (Figure 9A/B). The cholesterol levels were unchanged by any treatment as these levels were also comparable in the untreated db/db mice compared to the lean mice (Figure 9C)."	"In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPAR&gamma; in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo."
REF00088	PDC_00347	Type 2 diabetes	db/db mice model.	Obtained from the Model Organism Data	High Expreesion	Cholesterol level	2.8	.	.	.	.	.	.	.	.	.	Every day; over 8 days	2.5 &micro;M	.	"The influence of tesa, tesa-NPY (3), and [F7, P34]-NPY (2) on the plasma lipids was also analyzed (Figure 9). The vehicle/untreated db/db mice showed elevated levels of triglycerides and free fatty acids (FFA) compared to the lean C57BL/6N mice. Treatment with tesa and tesa-NPY (3) led to a normalization of the triglycerides, FFA, whereas [F7, P34]-NPY (2) and vehicle/untreated had no influence on the lipid metabolism (Figure 9A/B). The cholesterol levels were unchanged by any treatment as these levels were also comparable in the untreated db/db mice compared to the lean mice (Figure 9C)."	"In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPAR&gamma; in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells.Additionally, tesa-NPY induces adipocyte differentiation in vivo."
REF00083	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	77%	%	.	.	.	Patients with progressive disease (PD) on second-line hormonal therapy and/or docetaxel chemotherapy.	.	.	.	.	8- to 12-weekly intervals	3.7 to 8 GBq	.	"The disease control rates according to the radiographic and molecular response were 77% and 71%, respectively. The median overall survival and median progression-free survivals were 14 and 11.8 months, respectively. "	.
REF00084	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	14 months	months	.	.	.	Patients with progressive disease (PD) on second-line hormonal therapy and/or docetaxel chemotherapy.	.	.	.	.	8- to 12-weekly intervals	3.7 to 8 GBq	.	"The disease control rates according to the radiographic and molecular response were 77% and 71%, respectively. The median overall survival and median progression-free survivals were 14 and 11.8 months, respectively. "	.
REF00085	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	11.8 months	months	.	.	.	Patients with progressive disease (PD) on second-line hormonal therapy and/or docetaxel chemotherapy.	.	.	.	.	8- to 12-weekly intervals	3.7 to 8 GBq	.	"The disease control rates according to the radiographic and molecular response were 77% and 71%, respectively. The median overall survival and median progression-free survivals were 14 and 11.8 months, respectively. "	.
REF00086	PDC_00045	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	13.9 months	months	.	.	.	Patients with neuroendocrine tumor.	.	.	.	.	4 cycles	1.85 GBq/m<sup>2</sup>/cycle	.	"Median progression-free survival and overall survival (OS) were 13.9 and 22.3 mo, respectively."	.
REF00086	PDC_00045	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	22.3 months	months	.	.	.	Patients with neuroendocrine tumor.	.	.	.	.	4 cycles	1.85 GBq/m<sup>2</sup>/cycle	.	"Median progression-free survival and overall survival (OS) were 13.9 and 22.3 mo, respectively."	.
REF00087	PDC_00092	Malaria	Plasmodium falciparum W2.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	1.5 &micro;M	&micro;M	.	.	.	.	.	.	.	.	.	.	.	"Only three of the Cq-C4-CPP conjugates, namely, 5a, 5b, and 5g, displayed IC50 values below 10 &mu;M, with TP10- and Transportan-derived conjugates 5a (IC50 = 1.52 &mu;M) and 5b (IC50 = 5.20 &mu;M) being the most active. "	"The significant increase in the hemolytic activity of TP10 upon conjugation to the 4-aminoquinoline suggests that drug cargo prevents an otherwise active CPP carrier from exerting the desired cell penetrating/antiplasmodial action safely, as it produces conjugates that exert membranolytic activity."
REF00087	PDC_00092	Malaria	Plasmodium falciparum 3D7.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	0.8 &plusmn; 0.1 &micro;M	&micro;M	.	.	.	.	.	.	.	.	.	.	.	.	"The significant increase in the hemolytic activity of TP10 upon conjugation to the 4-aminoquinoline suggests that drug cargo prevents an otherwise active CPP carrier from exerting the desired cell penetrating/antiplasmodial action safely, as it produces conjugates that exert membranolytic activity."
REF00087	PDC_00093	Malaria	Plasmodium falciparum W2.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	5.2 &micro;M	&micro;M	.	.	.	.	.	.	.	.	.	.	.	"Only three of the Cq-C4-CPP conjugates, namely, 5a, 5b, and 5g, displayed IC50 values below 10 &mu;M, with TP10- and Transportan-derived conjugates 5a (IC50 = 1.52 &mu;M) and 5b (IC50 = 5.20 &mu;M) being the most active. "	"The significant increase in the hemolytic activity of TP10 upon conjugation to the 4-aminoquinoline suggests that drug cargo prevents an otherwise active CPP carrier from exerting the desired cell penetrating/antiplasmodial action safely, as it produces conjugates that exert membranolytic activity."
REF00087	PDC_00085	Malaria	Plasmodium falciparum W2.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	10 &micro;M	&micro;M	.	.	.	.	.	.	.	.	.	.	.	"Only three of the Cq-C4-CPP conjugates, namely, 5a, 5b, and 5g, displayed IC50 values below 10 &mu;M, with TP10- and Transportan-derived conjugates 5a (IC50 = 1.52 &mu;M) and 5b (IC50 = 5.20 &mu;M) being the most active. "	"The significant increase in the hemolytic activity of TP10 upon conjugation to the 4-aminoquinoline suggests that drug cargo prevents an otherwise active CPP carrier from exerting the desired cell penetrating/antiplasmodial action safely, as it produces conjugates that exert membranolytic activity."
REF00087	PDC_00086	Malaria	Plasmodium falciparum W2.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	10 &micro;M	&micro;M	.	.	.	.	.	.	.	.	.	.	.	"Only three of the Cq-C4-CPP conjugates, namely, 5a, 5b, and 5g, displayed IC50 values below 10 &mu;M, with TP10- and Transportan-derived conjugates 5a (IC50 = 1.52 &mu;M) and 5b (IC50 = 5.20 &mu;M) being the most active. "	"The significant increase in the hemolytic activity of TP10 upon conjugation to the 4-aminoquinoline suggests that drug cargo prevents an otherwise active CPP carrier from exerting the desired cell penetrating/antiplasmodial action safely, as it produces conjugates that exert membranolytic activity."
REF00087	PDC_00087	Malaria	Plasmodium falciparum W2.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	10 &micro;M	&micro;M	.	.	.	.	.	.	.	.	.	.	.	"Only three of the Cq-C4-CPP conjugates, namely, 5a, 5b, and 5g, displayed IC50 values below 10 &mu;M, with TP10- and Transportan-derived conjugates 5a (IC50 = 1.52 &mu;M) and 5b (IC50 = 5.20 &mu;M) being the most active. "	"The significant increase in the hemolytic activity of TP10 upon conjugation to the 4-aminoquinoline suggests that drug cargo prevents an otherwise active CPP carrier from exerting the desired cell penetrating/antiplasmodial action safely, as it produces conjugates that exert membranolytic activity."
REF00087	PDC_00091	Malaria	Plasmodium falciparum W2.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	10 &micro;M	&micro;M	.	.	.	.	.	.	.	.	.	.	.	"Only three of the Cq-C4-CPP conjugates, namely, 5a, 5b, and 5g, displayed IC50 values below 10 &mu;M, with TP10- and Transportan-derived conjugates 5a (IC50 = 1.52 &mu;M) and 5b (IC50 = 5.20 &mu;M) being the most active. "	"The significant increase in the hemolytic activity of TP10 upon conjugation to the 4-aminoquinoline suggests that drug cargo prevents an otherwise active CPP carrier from exerting the desired cell penetrating/antiplasmodial action safely, as it produces conjugates that exert membranolytic activity."
REF00087	PDC_00088	Malaria	Plasmodium falciparum W2.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	8.5 &micro;M	&micro;M	.	.	.	.	.	.	.	.	.	.	.	"Only three of the Cq-C4-CPP conjugates, namely, 5a, 5b, and 5g, displayed IC50 values below 10 &mu;M, with TP10- and Transportan-derived conjugates 5a (IC50 = 1.52 &mu;M) and 5b (IC50 = 5.20 &mu;M) being the most active. "	"The significant increase in the hemolytic activity of TP10 upon conjugation to the 4-aminoquinoline suggests that drug cargo prevents an otherwise active CPP carrier from exerting the desired cell penetrating/antiplasmodial action safely, as it produces conjugates that exert membranolytic activity."
REF00087	PDC_00090	Malaria	Plasmodium falciparum W2.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	10 &micro;M	&micro;M	.	.	.	.	.	.	.	.	.	.	.	"Only three of the Cq-C4-CPP conjugates, namely, 5a, 5b, and 5g, displayed IC50 values below 10 &mu;M, with TP10- and Transportan-derived conjugates 5a (IC50 = 1.52 &mu;M) and 5b (IC50 = 5.20 &mu;M) being the most active. "	"The significant increase in the hemolytic activity of TP10 upon conjugation to the 4-aminoquinoline suggests that drug cargo prevents an otherwise active CPP carrier from exerting the desired cell penetrating/antiplasmodial action safely, as it produces conjugates that exert membranolytic activity."
REF00087	PDC_00089	Malaria	Plasmodium falciparum W2.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	10 &micro;M	&micro;M	.	.	.	.	.	.	.	.	.	.	.	"Only three of the Cq-C4-CPP conjugates, namely, 5a, 5b, and 5g, displayed IC50 values below 10 &mu;M, with TP10- and Transportan-derived conjugates 5a (IC50 = 1.52 &mu;M) and 5b (IC50 = 5.20 &mu;M) being the most active. "	"The significant increase in the hemolytic activity of TP10 upon conjugation to the 4-aminoquinoline suggests that drug cargo prevents an otherwise active CPP carrier from exerting the desired cell penetrating/antiplasmodial action safely, as it produces conjugates that exert membranolytic activity."
REF00087	PDC_00084	Malaria	Plasmodium falciparum 3D7.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	0.8 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	.	.	.	.	.	.	.	.	"The significant increase in the hemolytic activity of TP10 upon conjugation to the 4-aminoquinoline suggests that drug cargo prevents an otherwise active CPP carrier from exerting the desired cell penetrating/antiplasmodial action safely, as it produces conjugates that exert membranolytic activity."
REF00087	PDC_00095	Malaria	Plasmodium falciparum 3D7.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	1.2 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	.	.	.	.	.	.	.	.	"The significant increase in the hemolytic activity of TP10 upon conjugation to the 4-aminoquinoline suggests that drug cargo prevents an otherwise active CPP carrier from exerting the desired cell penetrating/antiplasmodial action safely, as it produces conjugates that exert membranolytic activity."
REF00087	PDC_00094	Malaria	Plasmodium falciparum 3D7.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	1.0 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	.	.	.	.	.	.	.	.	"The significant increase in the hemolytic activity of TP10 upon conjugation to the 4-aminoquinoline suggests that drug cargo prevents an otherwise active CPP carrier from exerting the desired cell penetrating/antiplasmodial action safely, as it produces conjugates that exert membranolytic activity."
REF00082	PDC_00052	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	88%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	.	48 h	100 &micro;g/ml	MTT assay	"As evident from the cell viability assay, the blank nanoparticles containing covalently attached 5-Fu showed almost no toxicity even at a very high concentration of 500 &mu;g/mL, justifying the prodrug nature of the synthesized 5Fu-peptide nanoparticles. However, it showed a substantial amount of toxicity when irradiated with UV-light (365 nm). "	"This, as anticipated, may be attributed to the photo-induced release of the antitumor agent 5Fu from the nanoparticles, thereby killing the cancer cells."
REF00082	PDC_00052	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	84%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	.	48 h	200 &micro;g/ml	MTT assay	"As evident from the cell viability assay, the blank nanoparticles containing covalently attached 5-Fu showed almost no toxicity even at a very high concentration of 500 &mu;g/mL, justifying the prodrug nature of the synthesized 5Fu-peptide nanoparticles. However, it showed a substantial amount of toxicity when irradiated with UV-light (365 nm). "	"This, as anticipated, may be attributed to the photo-induced release of the antitumor agent 5Fu from the nanoparticles, thereby killing the cancer cells."
REF00082	PDC_00052	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	80%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	.	48 h	300 &micro;g/ml	MTT assay	"As evident from the cell viability assay, the blank nanoparticles containing covalently attached 5-Fu showed almost no toxicity even at a very high concentration of 500 &mu;g/mL, justifying the prodrug nature of the synthesized 5Fu-peptide nanoparticles. However, it showed a substantial amount of toxicity when irradiated with UV-light (365 nm). "	"This, as anticipated, may be attributed to the photo-induced release of the antitumor agent 5Fu from the nanoparticles, thereby killing the cancer cells."
REF00082	PDC_00052	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	75%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	.	48 h	400 &micro;g/ml	MTT assay	"As evident from the cell viability assay, the blank nanoparticles containing covalently attached 5-Fu showed almost no toxicity even at a very high concentration of 500 &mu;g/mL, justifying the prodrug nature of the synthesized 5Fu-peptide nanoparticles. However, it showed a substantial amount of toxicity when irradiated with UV-light (365 nm). "	"This, as anticipated, may be attributed to the photo-induced release of the antitumor agent 5Fu from the nanoparticles, thereby killing the cancer cells."
REF00082	PDC_00052	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	70%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	.	48 h	500 &micro;g/ml	MTT assay	"As evident from the cell viability assay, the blank nanoparticles containing covalently attached 5-Fu showed almost no toxicity even at a very high concentration of 500 &mu;g/mL, justifying the prodrug nature of the synthesized 5Fu-peptide nanoparticles. However, it showed a substantial amount of toxicity when irradiated with UV-light (365 nm). "	"This, as anticipated, may be attributed to the photo-induced release of the antitumor agent 5Fu from the nanoparticles, thereby killing the cancer cells."
REF00082	PDC_00052	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	73%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	.	48 h	100 &micro;g/ml;irradiated with UV-light (365 nm)	MTT assay	"As evident from the cell viability assay, the blank nanoparticles containing covalently attached 5-Fu showed almost no toxicity even at a very high concentration of 500 &mu;g/mL, justifying the prodrug nature of the synthesized 5Fu-peptide nanoparticles. However, it showed a substantial amount of toxicity when irradiated with UV-light (365 nm). "	"This, as anticipated, may be attributed to the photo-induced release of the antitumor agent 5Fu from the nanoparticles, thereby killing the cancer cells."
REF00082	PDC_00052	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	60%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	.	48 h	200 &micro;g/ml;irradiated with UV-light (365 nm)	MTT assay	"As evident from the cell viability assay, the blank nanoparticles containing covalently attached 5-Fu showed almost no toxicity even at a very high concentration of 500 &mu;g/mL, justifying the prodrug nature of the synthesized 5Fu-peptide nanoparticles. However, it showed a substantial amount of toxicity when irradiated with UV-light (365 nm). "	"This, as anticipated, may be attributed to the photo-induced release of the antitumor agent 5Fu from the nanoparticles, thereby killing the cancer cells."
REF00082	PDC_00052	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	58%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	.	48 h	300 &micro;g/ml;irradiated with UV-light (365 nm)	MTT assay	"As evident from the cell viability assay, the blank nanoparticles containing covalently attached 5-Fu showed almost no toxicity even at a very high concentration of 500 &mu;g/mL, justifying the prodrug nature of the synthesized 5Fu-peptide nanoparticles. However, it showed a substantial amount of toxicity when irradiated with UV-light (365 nm). "	"This, as anticipated, may be attributed to the photo-induced release of the antitumor agent 5Fu from the nanoparticles, thereby killing the cancer cells."
REF00082	PDC_00052	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	51%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	.	48 h	400 &micro;g/ml;irradiated with UV-light (365 nm)	MTT assay	"As evident from the cell viability assay, the blank nanoparticles containing covalently attached 5-Fu showed almost no toxicity even at a very high concentration of 500 &mu;g/mL, justifying the prodrug nature of the synthesized 5Fu-peptide nanoparticles. However, it showed a substantial amount of toxicity when irradiated with UV-light (365 nm). "	"This, as anticipated, may be attributed to the photo-induced release of the antitumor agent 5Fu from the nanoparticles, thereby killing the cancer cells."
REF00082	PDC_00052	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	50%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	.	48 h	500 &micro;g/ml;irradiated with UV-light (365 nm)	MTT assay	"As evident from the cell viability assay, the blank nanoparticles containing covalently attached 5-Fu showed almost no toxicity even at a very high concentration of 500 &mu;g/mL, justifying the prodrug nature of the synthesized 5Fu-peptide nanoparticles. However, it showed a substantial amount of toxicity when irradiated with UV-light (365 nm). "	"This, as anticipated, may be attributed to the photo-induced release of the antitumor agent 5Fu from the nanoparticles, thereby killing the cancer cells."
REF00077	PDC_00236	Glioma	.	Revealed Based on the Cell Line Data	.	Cell viability	60%	%	.	.	.	.	Glioblastoma	U-87MG cell	.	.	24 h	100 nM	MTS assay	Both PDCs showed higher in vitro cytotoxicity than free PTX.	.
REF00077	PDC_00236	Glioma	U87MG-Luc-bearing xenograft model.	Discovered Using Cell Line-derived Xenograft Model	.	Percent survival	0%	%	.	.	.	.	Glioblastoma	U87MG-Luc cell	.	.	25 days	Normalized to 17.3 mg/kg PTX	.	"The survival of the PTX group was markedly lower than that of the Vehicle group. M1-PTX did not improve survival, whereas the survival of the M1-RGD-PTX group was increased."	.
REF00077	PDC_00237	Glioma	.	Revealed Based on the Cell Line Data	.	Cell viability	55%	%	.	.	.	.	Glioblastoma	U-87MG cell	.	.	24 h	100 nM	MTS assay	Both PDCs showed higher in vitro cytotoxicity than free PTX.	.
REF00077	PDC_00237	Glioma	.	Revealed Based on the Cell Line Data	.	Median lethal dose (LD50)	152 mg/kg	mg/kg	.	.	.	.	Glioblastoma	U-87MG cell	.	.	24 h	100 nM	.	The fitted LD50 for M1-RGD-PTX was 152 mg/kg (equivalent to 60 mg/kg PTX). 	.
REF00077	PDC_00237	Glioma	U87MG-Luc-bearing xenograft model.	Discovered Using Cell Line-derived Xenograft Model	.	Percent survival	20%	%	.	.	.	.	Glioblastoma	U87MG-Luc cell	.	.	25 days	Normalized to 17.3 mg/kg PTX	.	"The survival of the PTX group was markedly lower than that of the Vehicle group. M1-PTX did not improve survival, whereas the survival of the M1-RGD-PTX group was increased."	.
REF00077	PDC_00237	Triple-negative breast cancer	MDA-MB-231BR mouse model.	Discovered Using Cell Line-derived Xenograft Model	.	Percent survival	50%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	20 days	44 mg/kg	.	"PTX did not increase survival, while the PDC M1-RGD-PTX markedly increased survival. "	.
REF00076	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	5.7 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer and liver metastases.	.	.	.	.	7-8 wk	6-7.5 MBq/cycle	.	Median estimated survival was 5.7 mo for <sup>177</sup>Lu-PSMA alone and 8.4 mo for combined sequential <sup>177</sup>Lu-PSMA and SIRT. 	.
REF00076	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	8.4 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer and liver metastases.	.	.	.	.	7-8 wk	6-7.5 MBq/cycle (Combined sequential 177Lu-PSMA and SIRT)	.	Median estimated survival was 5.7 mo for <sup>177</sup>Lu-PSMA alone and 8.4 mo for combined sequential <sup>177</sup>Lu-PSMA and SIRT. 	.
REF00071	PDC_00144	Medulloblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	25 &plusmn; 1.22 nM	nM	.	.	.	.	Medulloblastoma	Medulloblastoma cell	.	"In order to track them, protoporphyrin IX-labeled peptides, PpIX-RGD and PpIX-RAD, were synthesized (Figures S10 and S11) and then were coassemblied with NLG-RGD and NLG-RAD to prepare PpIXNLG-RGD NI and PpIXNLG-RAD NI (Table S2), respectively. After incubation with Pan02 cells for 0.5 h, PpIXNLG-RGD NI exhibited a stronger fluorescent signal than PpIXNLG-RAD NI, confirming its more efficient cellular uptake (Figure S16A). Moreover, a highly colocalized fluorescence of PpIX and Lysotracker was observed in both groups, suggesting that these internalized nanoinhibitors were further transported to lysosomes."	72 h	.	.	"This was confirmed with E1-7 doxorubicin conjugate (4) displaying a 5-fold reduction in cytotoxicity compared to E1-3 doxorubicin conjugate (3) (IC50 values of 130 &plusmn; 1.27 nM and 25 &plusmn; 1.22 nM, respectively) and 14-fold reduction in cytotoxicity compared to free doxorubicin (5) (IC50 values of 130 &plusmn; 1.27 nM and 8.8 &plusmn; 1.31 nM, respectively) (Figure 7)."	.
REF00071	PDC_00144	Medulloblastoma	Blood brain barrier model.	Obtained from the Model Organism Data	.	Blood-brain barrier permeability	8	.	.	.	.	.	Normal	HBEC-5i cell	.	"In order to track them, protoporphyrin IX-labeled peptides, PpIX-RGD and PpIX-RAD, were synthesized (Figures S10 and S11) and then were coassemblied with NLG-RGD and NLG-RAD to prepare PpIXNLG-RGD NI and PpIXNLG-RAD NI (Table S2), respectively. After incubation with Pan02 cells for 0.5 h, PpIXNLG-RGD NI exhibited a stronger fluorescent signal than PpIXNLG-RAD NI, confirming its more efficient cellular uptake (Figure S13A). Moreover, a highly colocalized fluorescence of PpIX and Lysotracker was observed in both groups, suggesting that these internalized nanoinhibitors were further transported to lysosomes."	30 min	.	.	"Notably, its permeability efficiency was significantly higher compared to free doxorubicin (5) (36.93 &plusmn; 0.7 uM and 28.93 &plusmn; 0.2 uM, respectively, p < 0.001) at 120 min post-treatment (Figure 8D)."	.
REF00071	PDC_00144	Medulloblastoma	Blood brain barrier model.	Obtained from the Model Organism Data	.	Blood-brain barrier permeability	20	.	.	.	.	.	Normal	HBEC-5i cell	.	"In order to track them, protoporphyrin IX-labeled peptides, PpIX-RGD and PpIX-RAD, were synthesized (Figures S10 and S11) and then were coassemblied with NLG-RGD and NLG-RAD to prepare PpIXNLG-RGD NI and PpIXNLG-RAD NI (Table S2), respectively. After incubation with Pan02 cells for 0.5 h, PpIXNLG-RGD NI exhibited a stronger fluorescent signal than PpIXNLG-RAD NI, confirming its more efficient cellular uptake (Figure S14A). Moreover, a highly colocalized fluorescence of PpIX and Lysotracker was observed in both groups, suggesting that these internalized nanoinhibitors were further transported to lysosomes."	60 min	.	.	"Notably, its permeability efficiency was significantly higher compared to free doxorubicin (5) (36.93 &plusmn; 0.7 uM and 28.93 &plusmn; 0.2 uM, respectively, p < 0.001) at 120 min post-treatment (Figure 8D)."	.
REF00071	PDC_00144	Medulloblastoma	Blood brain barrier model.	Obtained from the Model Organism Data	.	Blood-brain barrier permeability	37	.	.	.	.	.	Normal	HBEC-5i cell	.	"In order to track them, protoporphyrin IX-labeled peptides, PpIX-RGD and PpIX-RAD, were synthesized (Figures S10 and S11) and then were coassemblied with NLG-RGD and NLG-RAD to prepare PpIXNLG-RGD NI and PpIXNLG-RAD NI (Table S2), respectively. After incubation with Pan02 cells for 0.5 h, PpIXNLG-RGD NI exhibited a stronger fluorescent signal than PpIXNLG-RAD NI, confirming its more efficient cellular uptake (Figure S15A). Moreover, a highly colocalized fluorescence of PpIX and Lysotracker was observed in both groups, suggesting that these internalized nanoinhibitors were further transported to lysosomes."	120 min	.	.	"Notably, its permeability efficiency was significantly higher compared to free doxorubicin (5) (36.93 &plusmn; 0.7 uM and 28.93 &plusmn; 0.2 uM, respectively, p < 0.001) at 120 min post-treatment (Figure 8D)."	.
REF00071	PDC_00144	Medulloblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	10754 &plusmn; 1.38 nM	nM	.	.	.	.	Normal	MRC-5 cell	.	"In order to track them, protoporphyrin IX-labeled peptides, PpIX-RGD and PpIX-RAD, were synthesized (Figures S10 and S11) and then were coassemblied with NLG-RGD and NLG-RAD to prepare PpIXNLG-RGD NI and PpIXNLG-RAD NI (Table S2), respectively. After incubation with Pan02 cells for 0.5 h, PpIXNLG-RGD NI exhibited a stronger fluorescent signal than PpIXNLG-RAD NI, confirming its more efficient cellular uptake (Figure S17A). Moreover, a highly colocalized fluorescence of PpIX and Lysotracker was observed in both groups, suggesting that these internalized nanoinhibitors were further transported to lysosomes."	72 h	.	.	"E1-3 doxorubicin conjugate had a pronounced reduction in cytotoxicity (>72-fold reduction, IC50 value of 10754 &plusmn; 1.38 nM) compared to free doxorubicin (IC50 value of 148 &plusmn; 1.15 nM) in human fibroblasts. E1-7 doxorubicin was also able to reduce the cytotoxicity of doxorubicin on fibroblasts but not to the same degree as the E1-3 doxorubicin conjugate. E1-3 doxorubicin conjugate (3) also had reduced cytotoxicity compared to free doxorubicin (>7.4-fold reduction, IC50 values of 842 &plusmn; 1.10 nM and 113 &plusmn; 1.14 nM, respectively) in primary cultures of human astrocytes, a major cell type located in the brain and spinal cord. "	.
REF00071	PDC_00144	Medulloblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	842.0 &plusmn; 1.10 nM	nM	.	.	.	.	Glioma	Brain astrocytes	.	"In control cells without FPR1-GFP expression, both the green channel (FPR1-GFP) and the red channel (DEF) were blank (Figure 4A), suggesting that DEF could not permeate through the plasma membrane. DEF entered into the HeLa FPR1-GFP cells through internalization, with visible cytoplasmic distribution of the green fluorescence (Figure 4B). The intensity of red fluorescence was much higher in HeLa FPR1-GFP than in HeLa cells when incubated with DEF (Figure 4D). The Rr value (0.5) demonstrated that the internalized DEF was colocalized with FPR1-GFP (Figure 4C). "	72 h	.	.	"E1-3 doxorubicin conjugate had a pronounced reduction in cytotoxicity (>72-fold reduction, IC50 value of 10754 &plusmn; 1.38 nM) compared to free doxorubicin (IC50 value of 148 &plusmn; 1.15 nM) in human fibroblasts. E1-7 doxorubicin was also able to reduce the cytotoxicity of doxorubicin on fibroblasts but not to the same degree as the E1-3 doxorubicin conjugate. E1-3 doxorubicin conjugate (3) also had reduced cytotoxicity compared to free doxorubicin (>7.4-fold reduction, IC50 values of 842 &plusmn; 1.10 nM and 113 &plusmn; 1.14 nM, respectively) in primary cultures of human astrocytes, a major cell type located in the brain and spinal cord. "	.
REF00071	PDC_00145	Medulloblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	130 &plusmn; 1.27 nM	nM	.	.	.	.	Medulloblastoma	Medulloblastoma cell	.	.	72 h	.	.	"This was confirmed with E1-7 doxorubicin conjugate (4) displaying a 5-fold reduction in cytotoxicity compared to E1-3 doxorubicin conjugate (3) (IC50 values of 130 &plusmn; 1.27 nM and 25 &plusmn; 1.22 nM, respectively) and 14-fold reduction in cytotoxicity compared to free doxorubicin (5) (IC50 values of 130 &plusmn; 1.27 nM and 8.8 &plusmn; 1.31 nM, respectively) (Figure 7)."	.
REF00069	PDC_00072	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	5.6 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U87 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00072	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	3 &mu;M	&mu;M	.	.	.	.	Colon cancer	HT29 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00072	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	9.1 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00072	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	12.5 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U87 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds 1b and 3b demonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure 6). Importantly, 1b was more active than 3b demonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that 2b was less efficient than 1b but marginally more active than 3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that 3c is still significantly more active in U87 cells expressing integrin receptors. By contrast, 1c kept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to 1b. "	.
REF00069	PDC_00072	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	50.5 &mu;M	&mu;M	.	.	.	.	Colon cancer	HT29 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds 1b and 3b demonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure 6). Importantly, 1b was more active than 3b demonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that 2b was less efficient than 1b but marginally more active than 3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that 3c is still significantly more active in U87 cells expressing integrin receptors. By contrast, 1c kept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to 1b. "	.
REF00069	PDC_00072	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	53.4 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds 1b and 3b demonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure 6). Importantly, 1b was more active than 3b demonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that 2b was less efficient than 1b but marginally more active than 3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that 3c is still significantly more active in U87 cells expressing integrin receptors. By contrast, 1c kept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to 1b. "	.
REF00069	PDC_00326	Tumor	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	5.8 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U87 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00326	Tumor	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	9.2 &mu;M	&mu;M	.	.	.	.	Colon cancer	HT29 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00326	Tumor	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	5 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00326	Tumor	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	42.2 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U87 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds1band3bdemonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure6). Importantly,1bwas more active than3bdemonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that2bwas less efficient than1bbut marginally more active than3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that3cis still significantly more active in U87 cells expressing integrin receptors. By contrast,1ckept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to1b."	.
REF00069	PDC_00326	Tumor	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	100 &mu;M	&mu;M	.	.	.	.	Colon cancer	HT29 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds1band3bdemonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure6). Importantly,1bwas more active than3bdemonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that2bwas less efficient than1bbut marginally more active than3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that3cis still significantly more active in U87 cells expressing integrin receptors. By contrast,1ckept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to2b."	.
REF00069	PDC_00326	Tumor	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	25.1 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds1band3bdemonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure6). Importantly,1bwas more active than3bdemonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that2bwas less efficient than1bbut marginally more active than3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that3cis still significantly more active in U87 cells expressing integrin receptors. By contrast,1ckept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to3b."	.
REF00069	PDC_00070	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	3 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U87 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00070	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	9.2 &mu;M	&mu;M	.	.	.	.	Colon cancer	HT29 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00070	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	21.7 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00070	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	56.9 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U87 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds1band3bdemonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure6). Importantly,1bwas more active than3bdemonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that2bwas less efficient than1bbut marginally more active than3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that3cis still significantly more active in U87 cells expressing integrin receptors. By contrast,1ckept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to1b."	.
REF00069	PDC_00070	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	150 &mu;M	&mu;M	.	.	.	.	Colon cancer	HT29 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds1band3bdemonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure6). Importantly,1bwas more active than3bdemonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that2bwas less efficient than1bbut marginally more active than3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that3cis still significantly more active in U87 cells expressing integrin receptors. By contrast,1ckept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to1b."	.
REF00069	PDC_00070	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	150 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds1band3bdemonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure6). Importantly,1bwas more active than3bdemonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that2bwas less efficient than1bbut marginally more active than3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that3cis still significantly more active in U87 cells expressing integrin receptors. By contrast,1ckept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to1b."	.
REF00069	PDC_00071	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	3.9 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U87 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00071	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	11 &mu;M	&mu;M	.	.	.	.	Colon cancer	HT29 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00071	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	2.7 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00071	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	23.8 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U87 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds1band3bdemonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure6). Importantly,1bwas more active than3bdemonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that2bwas less efficient than1bbut marginally more active than3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that3cis still significantly more active in U87 cells expressing integrin receptors. By contrast,1ckept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to1b."	.
REF00069	PDC_00071	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	89.1 &mu;M	&mu;M	.	.	.	.	Colon cancer	HT29 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds1band3bdemonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure6). Importantly,1bwas more active than3bdemonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that2bwas less efficient than1bbut marginally more active than3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that3cis still significantly more active in U87 cells expressing integrin receptors. By contrast,1ckept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to1b."	.
REF00069	PDC_00071	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	7.8 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds1band3bdemonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure6). Importantly,1bwas more active than3bdemonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that2bwas less efficient than1bbut marginally more active than3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that3cis still significantly more active in U87 cells expressing integrin receptors. By contrast,1ckept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to1b."	.
REF00069	PDC_00106	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	2.5 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U87 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00106	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	5.4 &mu;M	&mu;M	.	.	.	.	Colon cancer	HT29 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00106	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	14.7 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	72 h	.	.	All dau-loaded conjugates showed high toxicity in all cell lines tested with EC50 values in the lower micromolar range.	.
REF00069	PDC_00106	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	49.4 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U87 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds1band3bdemonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure6). Importantly,1bwas more active than3bdemonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that2bwas less efficient than1bbut marginally more active than3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that3cis still significantly more active in U87 cells expressing integrin receptors. By contrast,1ckept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to1b."	.
REF00069	PDC_00106	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	150 &mu;M	&mu;M	.	.	.	.	Colon cancer	HT29 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds1band3bdemonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure6). Importantly,1bwas more active than3bdemonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that2bwas less efficient than1bbut marginally more active than3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that3cis still significantly more active in U87 cells expressing integrin receptors. By contrast,1ckept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to1b."	.
REF00069	PDC_00106	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	150 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	15 min	.	.	"More specifically, compounds1band3bdemonstrated significantly higher activity against U87 cells compared to MCF-7 and HT-29 cells (Figure6). Importantly,1bwas more active than3bdemonstrating that the attached CPP is indeed necessary to increase the overall cellular uptake and thus cytotoxic activity of the conjugates. Of note is also that2bwas less efficient than1bbut marginally more active than3b, although with no selectivity. For the two conjugates bearing the GFLG motif, it was seen that3cis still significantly more active in U87 cells expressing integrin receptors. By contrast,1ckept its selectivity against HT-29 cells, but was pronouncedly more active in MCF-7 cells compared to1b."	.
REF00068	PDC_00241	Hepatocellular carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Time to disease progression	134 Day	Day	.	.	.	Patients with hepatocellular carcinoma who progressed on or after treatment with sorafenib or intolerant of sorafenib.	.	.	.	.	"Days 1, 2, and 3 of a 28-day cycle"	40 mg/m<sup>2</sup>	.	"The median TTP was 134.0 days, median PFS was 129.0 days, and median OS was 205.0 days."	.
REF00062	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	57.00%	%	.	.	.	Patients with advanced metastatic castration-resistant prostate cancer.	.	.	.	.	1 cycle	6 GBq	.	"During treatment, maximum prostate-specific antigen decrease was 50% or greater and 90% or greater in 57% and 24% of the patients, respectively. "	.
REF00062	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	11.3 months	months	.	.	.	Patients with advanced metastatic castration-resistant prostate cancer.	.	.	.	.	1 cycle	6 GBq	.	"During a median follow-up length of 13.7 months (range, 9.8-32.3 months), median overall survival from start of the first therapy cycle was 11.3 months (range, 1.4-32.3 months)."	.
REF00060	PDC_00097	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	68.5 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"After the MDA-MB-231 cell line was confirmed to be integrin v3-positive by immunofluorescence assay, it was demonstrated that cRGD-SMCC-DM1 had an IC50 value of 68.5 nM to MDA-MB-231 cells."	.
REF00060	PDC_00097	Breast cancer	Tumor-bearing nude mice.	Obtained from the Model Organism Data	High Expreesion	Tumer volume	1000 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	21d	.	.	.	.
REF00060	PDC_00097	Breast cancer	Tumor-bearing nude mice.	Obtained from the Model Organism Data	High Expreesion	ALT level	60	.	.	.	.	.	.	.	.	.	21d	.	.	"Remarkably, leucopenia and myelosuppression did not occur during the use of PDC. In addition, the values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), as the biomarkers of hepatic function, were all in the normal range in comparison to the saline group (Figure 5F-H). Meanwhile, normal renal function was also identified after treatment by monitoring CREA, UA, and BUN (Figure 5I-K)."	.
REF00060	PDC_00097	Breast cancer	Tumor-bearing nude mice.	Obtained from the Model Organism Data	High Expreesion	AST level	175	.	.	.	.	.	.	.	.	.	21d	.	.	"Remarkably, leucopenia and myelosuppression did not occur during the use of PDC. In addition, the values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), as the biomarkers of hepatic function, were all in the normal range in comparison to the saline group (Figure 5F-H). Meanwhile, normal renal function was also identified after treatment by monitoring CREA, UA, and BUN (Figure 5I-K)."	.
REF00060	PDC_00097	Breast cancer	Tumor-bearing nude mice.	Obtained from the Model Organism Data	High Expreesion	ALP level	80	.	.	.	.	.	.	.	.	.	21d	.	.	"Remarkably, leucopenia and myelosuppression did not occur during the use of PDC. In addition, the values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), as the biomarkers of hepatic function, were all in the normal range in comparison to the saline group (Figure 5F-H). Meanwhile, normal renal function was also identified after treatment by monitoring CREA, UA, and BUN (Figure 5I-K)."	.
REF00060	PDC_00097	Breast cancer	Tumor-bearing nude mice.	Obtained from the Model Organism Data	High Expreesion	Uric acid levels	185	.	.	.	.	.	.	.	.	.	21d	.	.	"Remarkably, leucopenia and myelosuppression did not occur during the use of PDC. In addition, the values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), as the biomarkers of hepatic function, were all in the normal range in comparison to the saline group (Figure 5F-H). Meanwhile, normal renal function was also identified after treatment by monitoring CREA, UA, and BUN (Figure 5I-K)."	.
REF00060	PDC_00097	Breast cancer	Tumor-bearing nude mice.	Obtained from the Model Organism Data	High Expreesion	BUN level	7	.	.	.	.	.	.	.	.	.	21d	.	.	"Remarkably, leucopenia and myelosuppression did not occur during the use of PDC. In addition, the values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), as the biomarkers of hepatic function, were all in the normal range in comparison to the saline group (Figure 5F-H). Meanwhile, normal renal function was also identified after treatment by monitoring CREA, UA, and BUN (Figure 5I-K)."	.
REF00059	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Serum creatinine level	0.8 mg/dL	mg/dL	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 cycles	4 GBq/cycle	.	"However, excellent response was noted and serum creatinine level of 0.8 mg/dL remained stable."	.
REF00058	PDC_00129	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.69 nM	nM	.	.	.	.	Normal	HEK293 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after 8h. On the other hand, GSHG resulted in increasing levels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"The presented data show that 2G2, 2G1 and GSHG bind to GnRH-R with 95.5-, 15.2-, and 4.4-fold higher affinity, respectively, than that of the native peptide D-Lys6-GnRH (10.5 &plusmn; 0.2 nM, according to our former study [3]). "	.
REF00058	PDC_00129	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	40000 nM	nM	.	.	.	.	Prostate carcinoma	DU145 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after 9h. On the other hand, GSHG resulted in increasinevels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"GSHGpossesses the highest cytotoxic effect among the three conjugates, which is comparable with that of gemcitabine in the examined cell lines and especially regarding MCF-7 cells."	.
REF00058	PDC_00129	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	40000 nM	nM	.	.	.	.	Prostate carcinoma	PC-3 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after10h. On the other hand, GSHG resulted in increasinevels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"GSHGpossesses the highest cytotoxic effect among the three conjugates, which is comparable with that of gemcitabine in the examined cell lines and especially regarding MCF-7 cells."	.
REF00058	PDC_00129	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	40000 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after11h. On the other hand, GSHG resulted in increasinevels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"GSHGpossesses the highest cytotoxic effect among the three conjugates, which is comparable with that of gemcitabine in the examined cell lines and especially regarding MCF-7 cells."	.
REF00058	PDC_00129	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	621.3 nM	nM	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after12h. On the other hand, GSHG resulted in increasinevels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"GSHGpossesses the highest cytotoxic effect among the three conjugates, which is comparable with that of gemcitabine in the examined cell lines and especially regarding MCF-7 cells."	.
REF00058	PDC_00130	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.11 nM	nM	.	.	.	.	Normal	HEK293 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after16h. On the other hand, GSHG resulted in increasinevels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"The presented data show that 2G2, 2G1 and GSHG bind to GnRH-R with 95.5-, 15.2-, and 4.4-fold higher affinity, respectively, than that of the native peptide D-Lys6-GnRH (10.5 &plusmn; 0.2 nM, according to our former study [3]). "	.
REF00058	PDC_00130	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9761 nM	nM	.	.	.	.	Prostate carcinoma	DU145 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after17h. On the other hand, GSHG resulted in increasinevels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"GSHGpossesses the highest cytotoxic effect among the three conjugates, which is comparable with that of gemcitabine in the examined cell lines and especially regarding MCF-7 cells."	.
REF00058	PDC_00130	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	40000 nM	nM	.	.	.	.	Prostate carcinoma	PC-3 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after18h. On the other hand, GSHG resulted in increasin"	.	.	.	"GSHGpossesses the highest cytotoxic effect among the three conjugates, which is comparable with that of gemcitabine in the examined cell lines and especially regarding MCF-7 cells."	.
REF00058	PDC_00130	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	40000 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after19h. On the other hand, GSHG resulted in increasinevels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"GSHGpossesses the highest cytotoxic effect among the three conjugates, which is comparable with that of gemcitabine in the examined cell lines and especially regarding MCF-7 cells."	.
REF00058	PDC_00130	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	449.1 nM	nM	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after20h. On the other hand, GSHG resulted in increasinevels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"GSHGpossesses the highest cytotoxic effect among the three conjugates, which is comparable with that of gemcitabine in the examined cell lines and especially regarding MCF-7 cells."	.
REF00058	PDC_00131	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.40 nM	nM	.	.	.	.	Normal	HEK293 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after24h. On the other hand, GSHG resulted in increasinevels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"The presented data show that 2G2, 2G1 and GSHG bind to GnRH-R with 95.5-, 15.2-, and 4.4-fold higher affinity, respectively, than that of the native peptide D-Lys6-GnRH (10.5 &plusmn; 0.2 nM, according to our former study [3]). "	.
REF00058	PDC_00131	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	684 nM	nM	.	.	.	.	Prostate carcinoma	DU145 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after25h. On the other hand, GSHG resulted in increasinevels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"GSHGpossesses the highest cytotoxic effect among the three conjugates, which is comparable with that of gemcitabine in the examined cell lines and especially regarding MCF-7 cells."	.
REF00058	PDC_00131	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	937 nM	nM	.	.	.	.	Prostate carcinoma	PC-3 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after26h. On the other hand, GSHG resulted in increasinevels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"GSHGpossesses the highest cytotoxic effect among the three conjugates, which is comparable with that of gemcitabine in the examined cell lines and especially regarding MCF-7 cells."	.
REF00058	PDC_00131	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2387 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after27h. On the other hand, GSHG resulted in increasinevels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"GSHGpossesses the highest cytotoxic effect among the three conjugates, which is comparable with that of gemcitabine in the examined cell lines and especially regarding MCF-7 cells."	.
REF00058	PDC_00131	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	55.5 nM	nM	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"Incubation of 2G1 and 2G2 in cancer cell lines DU145 did not result in intracellular detection of gemcitabine, suggesting again that this linkage is very stable and gemcitabine was not released even after28h. On the other hand, GSHG resulted in increasinevels of gemcitabine over time (Fig. 4B), resulting in a relatively rapid release of the drug."	.	.	.	"GSHGpossesses the highest cytotoxic effect among the three conjugates, which is comparable with that of gemcitabine in the examined cell lines and especially regarding MCF-7 cells."	.
REF00081	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>90% PSA decline	64.00%	%	.	.	.	Patients with PSMA-avid metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles; every 6 wk	7.5 GBq/cycle	.	"A PSA decline of at least 50% was achieved in 32 of 50 patients (64%; 95% confidence interval [CI], 50%-77%), including 22 patients (44%; 95% CI, 30%-59%) with at least an 80% decrease. "	.
REF00081	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	13.3 months	months	.	.	.	Patients with PSMA-avid metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles; every 6 wk	7.5 GBq/cycle	.	"median overall survival was 13.3 mo (95% CI, 10.5-18.7 mo)"	.
REF00080	PDC_00303	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.3 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	MTT assay	"The results showed that the cytotoxicity of both conjugates 1 and 2 (IC50 = 1.3 and 2.2 uM, respectively), as well as the free Dox (IC50 = 1.5 uM) on MDA-MB-231 breast cancer cell line, were in the low micromolar range (Figure 4). For the breast cancer cell line MDA-MB-468, the free Dox (IC50 = 0.35 uM) was slightly more toxic compared to conjugates 1 (4.7 uM) and 2 (1.2 uM). For the non-cancerous cell line MCF 10A, the free Dox was highly toxic (IC50 = 0.24 uM) whereas conjugates 1 and 2 displayed much-reduced toxicity (IC50 = 38.6 and 15.1 uM, respectively). "	.
REF00080	PDC_00303	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.7 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	.	.	MTT assay	"The results showed that the cytotoxicity of both conjugates 1 and 2 (IC50 = 1.3 and 2.2 uM, respectively), as well as the free Dox (IC50 = 1.5 uM) on MDA-MB-231 breast cancer cell line, were in the low micromolar range (Figure 4). For the breast cancer cell line MDA-MB-468, the free Dox (IC50 = 0.35 uM) was slightly more toxic compared to conjugates 1 (4.7 uM) and 2 (1.2 uM). For the non-cancerous cell line MCF 10A, the free Dox was highly toxic (IC50 = 0.24 uM) whereas conjugates 1 and 2 displayed much-reduced toxicity (IC50 = 38.6 and 15.1 uM, respectively). "	.
REF00080	PDC_00303	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	38.6 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	.	.	MTT assay	"The results showed that the cytotoxicity of both conjugates 1 and 2 (IC50 = 1.3 and 2.2 uM, respectively), as well as the free Dox (IC50 = 1.5 uM) on MDA-MB-231 breast cancer cell line, were in the low micromolar range (Figure 4). For the breast cancer cell line MDA-MB-468, the free Dox (IC50 = 0.35 uM) was slightly more toxic compared to conjugates 1 (4.7 uM) and 2 (1.2 uM). For the non-cancerous cell line MCF 10A, the free Dox was highly toxic (IC50 = 0.24 uM) whereas conjugates 1 and 2 displayed much-reduced toxicity (IC50 = 38.6 and 15.1 uM, respectively). "	.
REF00080	PDC_02117	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.2 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	MTT assay	"The results showed that the cytotoxicity of both conjugates 1 and 2 (IC50 = 1.3 and 2.2 uM, respectively), as well as the free Dox (IC50 = 1.5 uM) on MDA-MB-231 breast cancer cell line, were in the low micromolar range (Figure 4). For the breast cancer cell line MDA-MB-468, the free Dox (IC50 = 0.35 uM) was slightly more toxic compared to conjugates 1 (4.7 uM) and 2 (1.2 uM). For the non-cancerous cell line MCF 10A, the free Dox was highly toxic (IC50 = 0.24 uM) whereas conjugates 1 and 2 displayed much-reduced toxicity (IC50 = 38.6 and 15.1 uM, respectively). "	.
REF00080	PDC_02117	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.2 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	.	.	MTT assay	"The results showed that the cytotoxicity of both conjugates 1 and 2 (IC50 = 1.3 and 2.2 uM, respectively), as well as the free Dox (IC50 = 1.5 uM) on MDA-MB-231 breast cancer cell line, were in the low micromolar range (Figure 4). For the breast cancer cell line MDA-MB-468, the free Dox (IC50 = 0.35 uM) was slightly more toxic compared to conjugates 1 (4.7 uM) and 2 (1.2 uM). For the non-cancerous cell line MCF 10A, the free Dox was highly toxic (IC50 = 0.24 uM) whereas conjugates 1 and 2 displayed much-reduced toxicity (IC50 = 38.6 and 15.1 uM, respectively). "	.
REF00080	PDC_02117	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.1 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	.	.	MTT assay	"The results showed that the cytotoxicity of both conjugates 1 and 2 (IC50 = 1.3 and 2.2 uM, respectively), as well as the free Dox (IC50 = 1.5 uM) on MDA-MB-231 breast cancer cell line, were in the low micromolar range (Figure 4). For the breast cancer cell line MDA-MB-468, the free Dox (IC50 = 0.35 uM) was slightly more toxic compared to conjugates 1 (4.7 uM) and 2 (1.2 uM). For the non-cancerous cell line MCF 10A, the free Dox was highly toxic (IC50 = 0.24 uM) whereas conjugates 1 and 2 displayed much-reduced toxicity (IC50 = 38.6 and 15.1 uM, respectively). "	.
REF00079	PDC_00067	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.21 &plusmn; 1.12 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	"As shown in Fig. 2, there was little difference in the intracellular fluorescence intensity of DOX in both cell lines (mean fluorescence intensity, MFI 721.71 for HepG2 cells and 772.06 for L-O2 cells, respectively) after treatment with free DOX for 3 h, whereas the intracellular fluorescence intensity of DOX produced from the BP9a-SS-DOX conjugate in HepG2 cells (MFI 278.44, Fig. 2a) was higher than that in L-O2 cells (MFI 58.43, Fig. 2b) when cells were incubated with the conjugate for 3 h, indicating that the specific cellular uptake of the BP9a-SS-DOX conjugate by cells expressing higher level of TfR."	.	.	CCK-8 assay	The BP9a-SS-DOX conjugate exhibited impressed antiproliferative activity against HepG2 cells with an IC50 value of 6.21 &plusmn; 1.12 uM which was lower than that of free DOX.	.
REF00078	PDC_00302	Small cell lung cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.06 &micro;mol/L	&micro;mol/L	.	.	.	.	Lung small cell carcinoma	NCI-H524 cell	.	.	6 h	.	.	"PEN-221 receptor dependent activity in vitro varied from strong (NCI-H524) to modest (HCC-33) but was consistent (N = 3) and correlated with in vivo activity (described below). Octreotide alone did not have an effect on cellular growth. These cell lines also demonstrated sensitivity to the cytotoxic payload, DM1, with sub-micromolar IC50's after a 6-hour exposure and 70-hour additional incubation period (Supplementary Fig. S2B)."	.
REF00078	PDC_00302	Small cell lung cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.108 &micro;mol/L	&micro;mol/L	.	.	.	.	Small cell lung carcinoma	NCI-H69 cell	.	.	6 h	.	.	"PEN-221 receptor dependent activity in vitro varied from strong (NCI-H524) to modest (HCC-33) but was consistent (N = 3) and correlated with in vivo activity (described below). Octreotide alone did not have an effect on cellular growth. These cell lines also demonstrated sensitivity to the cytotoxic payload, DM1, with sub-micromolar IC50's after a 6-hour exposure and 70-hour additional incubation period (Supplementary Fig. S2B)."	.
REF00078	PDC_00302	Small cell lung cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.658 &micro;mol/L	&micro;mol/L	.	.	.	.	Lung small cell carcinoma	HCC33 cell	.	.	6 h	.	.	"PEN-221 receptor dependent activity in vitro varied from strong (NCI-H524) to modest (HCC-33) but was consistent (N = 3) and correlated with in vivo activity (described below). Octreotide alone did not have an effect on cellular growth. These cell lines also demonstrated sensitivity to the cytotoxic payload, DM1, with sub-micromolar IC50's after a 6-hour exposure and 70-hour additional incubation period (Supplementary Fig. S2B)."	.
REF00078	PDC_00302	Small cell lung cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.333 &micro;mol/L	&micro;mol/L	.	.	.	.	Lung small cell carcinoma	NCI-H524 cell	.	.	6 h	.	.	"PEN-221 receptor dependent activity in vitro varied from strong (NCI-H524) to modest (HCC-33) but was consistent (N = 3) and correlated with in vivo activity (described below). Octreotide alone did not have an effect on cellular growth. These cell lines also demonstrated sensitivity to the cytotoxic payload, DM1, with sub-micromolar IC50's after a 6-hour exposure and 70-hour additional incubation period (Supplementary Fig. S2B)."	.
REF00078	PDC_00302	Small cell lung cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.258 &micro;mol/L	&micro;mol/L	.	.	.	.	Small cell lung carcinoma	NCI-H69 cell	.	.	6 h	.	.	"PEN-221 receptor dependent activity in vitro varied from strong (NCI-H524) to modest (HCC-33) but was consistent (N = 3) and correlated with in vivo activity (described below). Octreotide alone did not have an effect on cellular growth. These cell lines also demonstrated sensitivity to the cytotoxic payload, DM1, with sub-micromolar IC50's after a 6-hour exposure and 70-hour additional incubation period (Supplementary Fig. S2B)."	.
REF00078	PDC_00302	Small cell lung cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.83 &micro;mol/L	&micro;mol/L	.	.	.	.	Lung small cell carcinoma	HCC33 cell	.	.	6 h	.	.	"PEN-221 receptor dependent activity in vitro varied from strong (NCI-H524) to modest (HCC-33) but was consistent (N = 3) and correlated with in vivo activity (described below). Octreotide alone did not have an effect on cellular growth. These cell lines also demonstrated sensitivity to the cytotoxic payload, DM1, with sub-micromolar IC50's after a 6-hour exposure and 70-hour additional incubation period (Supplementary Fig. S2B)."	.
REF00075	PDC_00205	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.8 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	16.5 &plusmn; 1.2 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.3 &plusmn; 0.9 &micro;M	&micro;M	.	.	.	.	Mammary carcinoma	4T1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Colon cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.5 &plusmn; 1.7 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Normal	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.6 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Normal	C-26 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Prostate carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.3 &plusmn; 0.4 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	DU145 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Prostate carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.3 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.0 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U-87MG cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.4 &plusmn; 1.1 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Ovarian serous adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	46.0 &plusmn; 1.3 &micro;M	&micro;M	.	.	.	.	Ovarian serous adenocarcinoma	OVCAR-3 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	High grade ovarian serous adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.7 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	High grade ovarian serous adenocarcinoma	OVCAR-8 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Hepatoblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.8 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.4 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	Melanoma	A2058 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	12.7 &plusmn; 1.5 &micro;M	&micro;M	.	.	.	.	Melanoma	WM983B cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Amelanotic melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	13.5 &plusmn; 1.1 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	HT168-M1/M9 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Amelanotic melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	16.2 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	M24 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.2 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	Melanoma	B16 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Oral cavity squamous cell carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.7 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	Oral cavity squamous cell carcinoma	PE/CA-PJ41	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Tongue squamous cell carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.4 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	Tongue squamous cell carcinoma	PE/CA-PJ15 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Lung adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.1 &plusmn; 0.1 &micro;M	&micro;M	.	.	.	.	Lung adenocarcinoma	H1975 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Minimally invasive lung adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.5 &plusmn; 1.1 &micro;M	&micro;M	.	.	.	.	Minimally invasive lung adenocarcinoma	H1650 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Lung adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.7 &plusmn; 0.6 &micro;M	&micro;M	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Pancreatic ductal adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Normal	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	41.9 &plusmn; 3.8 &micro;M	&micro;M	.	.	.	.	Normal	MRC-5 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00205	Breast cancer	Orthotopic 4T1 mice breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Proliferation index	16.30%	%	.	.	.	.	Breast cancer	4T1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	It was observed that both GnRH-III conjugates 1 and 2 caused a significant decrease of the proliferation index by 16.3 and 25.9%	.
REF00075	PDC_00205	Breast cancer	Orthotopic 4T1 mice breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Number of macro-metastases decrease	72.80%	%	.	.	.	.	Breast cancer	4T1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	"The number of macro-metastases in peripheral organs, such as spleen, lung, liver and kidneys, was counted, in order to determine the anti-metastatic effect of free Dau and the GnRH-III conjugates on aggressive 4T1 BC orthotopic model (Figure 5A). The number of macro-metastases in spleen was significantly decreased in all treated groups (Dau, 1 and 2) by 64.3, 72.8 and 78.1%. In the lung, the number of macro-metastases was also significantly reduced for all treated groups by 55.4, 55.2 and 64.4%, respectively. The numbers of macro-metastases in the liver and kidneys were decreased under treatments, whereby a significant decrease could be only obtained for conjugate 2."	.
REF00075	PDC_00205	Breast cancer	Orthotopic 4T1 mice breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Number of macro-metastases decrease	55.20%	%	.	.	.	.	Breast cancer	4T1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	"The number of macro-metastases in peripheral organs, such as spleen, lung, liver and kidneys, was counted, in order to determine the anti-metastatic effect of free Dau and the GnRH-III conjugates on aggressive 4T1 BC orthotopic model (Figure 5A). The number of macro-metastases in spleen was significantly decreased in all treated groups (Dau,1and2) by 64.3, 72.8 and 78.1%. In the lung, the number of macro-metastases was also significantly reduced for all treated groups by 55.4, 55.2 and 64.4%, respectively. The numbers of macro-metastases in the liver and kidneys were decreased under treatments, whereby a significant decrease could be only obtained for conjugate2."	.
REF00075	PDC_00205	Breast cancer	Orthotopic 4T1 mice breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Micro-metastases decrease	43.80%	%	.	.	.	.	Breast cancer	4T1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	"The obtained data revealed that free Dau and both conjugates (1, 2) significantly inhibited the number of micro-metastases in the lung by 33.7, 43.8 and 49.4%, as compared to the control group. The proliferation index of lung metastases was significantly inhibited by 27.8, 37 and 39.1% in groups that were treated with free Dau, 1 and 2."	.
REF00075	PDC_00205	Breast cancer	Orthotopic 4T1 mice breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Proliferation index	37%	%	.	.	.	.	Breast cancer	4T1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	"The obtained data revealed that free Dau and both conjugates (1, 2) significantly inhibited the number of micro-metastases in the lung by 33.7, 43.8 and 49.4%, as compared to the control group. The proliferation index of lung metastases was significantly inhibited by 27.8, 37 and 39.1% in groups that were treated with free Dau, 1 and 2."	.
REF00075	PDC_00205	Breast cancer	Orthotopic MDA-MB-231 human breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Body weigth change	10.10%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	15 mg/kg Dau content	.	"The body weight of the mice in control group was decreased by 2.7%, while in the groups treated with 1 and 2, it was decreased by 10.1 and 8.2%."	.
REF00075	PDC_00205	Breast cancer	Orthotopic MDA-MB-231 human breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor volume decrease	34.10%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	15 mg/kg Dau content	.	"Apart from that, a significant inhibition of the tumor volume was also obtained in groups which were treated with conjugate 1 (34.1%) and 2 (23.1%)."	.
REF00075	PDC_00205	Breast cancer	Orthotopic MDA-MB-231 human breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	34.10%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	15 mg/kg Dau content	.	"Apart from that, a significant inhibition of the tumor volume was also obtained in groups which were treated with conjugate 1 (34.1%) and 2 (23.1%)."	.
REF00075	PDC_00205	Breast cancer	Orthotopic MDA-MB-231 human breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor weight decrease	28.70%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	15 mg/kg Dau content	.	"Based on these tumor weights, we determined that free Dau, 1 and 2 inhibited tumor weight significantly by 40.1, 28.7 and 27.7% in the case of orthotopic human MDA-MB-231 breast tumor model."	.
REF00075	PDC_00205	Breast cancer	Orthotopic MDA-MB-231 human breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	28.70%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	15 mg/kg Dau content	.	"Based on these tumor weights, we determined that free Dau, 1 and 2 inhibited tumor weight significantly by 40.1, 28.7 and 27.7% in the case of orthotopic human MDA-MB-231 breast tumor model."	.
REF00075	PDC_00205	Colorectal cancer	Orthotopic HT-29 human colon carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor weight	80.80%	%	.	.	.	.	Colon adenocarcinoma	HT-29 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	"The obtained data reveal that Dau, 1 and 2 significantly inhibited the tumor growth, whereby the tumor weights were reduced by 84.3, 80.8 and 87.1%, as compared to the control group."	.
REF00075	PDC_00205	Colorectal cancer	Orthotopic HT-29 human colon carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	80.80%	%	.	.	.	.	Colon adenocarcinoma	HT-29 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	"The obtained data reveal that Dau, 1 and 2 significantly inhibited the tumor growth, whereby the tumor weights were reduced by 84.3, 80.8 and 87.1%, as compared to the control group."	.
REF00075	PDC_00180	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.9 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.0 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.8 &plusmn; 0.1 &micro;M	&micro;M	.	.	.	.	Mammary carcinoma	4T1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Colon cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.3 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Normal	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.6 &plusmn; 0.7 &micro;M	&micro;M	.	.	.	.	Normal	C-26 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Prostate carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.1 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	DU145 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Prostate carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.4 &plusmn; 0.6 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.3 &plusmn; 0.1 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U-87MG cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.1 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Ovarian serous adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.2 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Ovarian serous adenocarcinoma	OVCAR-3 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	High grade ovarian serous adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.5 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	High grade ovarian serous adenocarcinoma	OVCAR-8 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Hepatoblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.2 &plusmn; 0.7 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.6 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Melanoma	A2058 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.6 &plusmn; 0.6 &micro;M	&micro;M	.	.	.	.	Melanoma	WM983B cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Amelanotic melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.9 &plusmn; 0.6 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	HT168-M1/M9 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Amelanotic melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.5 &plusmn; 0.6 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	M24 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.1 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Melanoma	B16 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Oral cavity squamous cell carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.7 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Oral cavity squamous cell carcinoma	PE/CA-PJ41	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Tongue squamous cell carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.9 &plusmn; 0.6 &micro;M	&micro;M	.	.	.	.	Tongue squamous cell carcinoma	PE/CA-PJ15 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Lung adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.3 &plusmn; 0.7 &micro;M	&micro;M	.	.	.	.	Lung adenocarcinoma	H1975 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Minimally invasive lung adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.0 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	Minimally invasive lung adenocarcinoma	H1650 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Lung adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.3 &plusmn; 0.4 &micro;M	&micro;M	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Pancreatic ductal adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	56.4 &plusmn; 4.5 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Normal	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	19.7 &plusmn; 1.2 &micro;M	&micro;M	.	.	.	.	Normal	MRC-5 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	24 h	.	.	"The anti-proliferative effect of the GnRH-III conjugates 1 and 2, as well as free Dau, was tested on wide range of cancer cell lines from different origin and also on MRC-5 (human fibroblast) as non-cancerous control cell line. The data showed that both conjugates possess an anti-proliferative effect on all cell types (Table 1). Except for the ovarian cancer cell lines A2780 and OVCAR-8, conjugate 2 displayed higher anti-proliferative activity than conjugate 1, depending on the type of cancer cells. The lowest activity was measured on PANC-1 pancreatic cancer cells, whereby a high IC50 value was also obtained on MRC-5 cells, showing selectivity of the conjugates for cancer cell lines. The obtained IC50 values of the conjugates vary mostly in the low micromolar range and were one to two order of magnitude higher when compared to free Dau that can enter cells non-specifically by passive diffusion. Moreover, the relative potency was calculated as a ratio of conjugates IC50 and free Daus IC50 in order to show the potency of the conjugates independently from the cell line, due to different activity of free Dau. A lower value of relative potency indicates that the conjugates IC50 value is closer to the free Daus IC50 value, which implies that the targeting capacity of the conjugate as well as its anti-tumor effect is stronger on a particular cell line, as compared to a cell line with higher relative potency. The BC cell lines showed good response to the conjugates by IC50 values, as well as by relative potency. Besides, the conjugates showed high anti-proliferative activity on mice CRC cell line C26, while the conjugates showed a moderate anti-proliferative activity on HT-29 human colon adenocarcinoma, but the relative potency was in the same range as for the BC cells."	.
REF00075	PDC_00180	Breast cancer	Orthotopic 4T1 mice breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Proliferation index	25.90%	%	.	.	.	.	Breast cancer	4T1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	It was observed that both GnRH-III conjugates 1 and 2 caused a significant decrease of the proliferation index by 16.3 and 25.9%	.
REF00075	PDC_00180	Breast cancer	Orthotopic 4T1 mice breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Number of macro-metastases decrease	78.10%	%	.	.	.	.	Breast cancer	4T1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	"The number of macro-metastases in peripheral organs, such as spleen, lung, liver and kidneys, was counted, in order to determine the anti-metastatic effect of free Dau and the GnRH-III conjugates on aggressive 4T1 BC orthotopic model (Figure 5A). The number of macro-metastases in spleen was significantly decreased in all treated groups (Dau, 1 and 2) by 64.3, 72.8 and 78.1%. In the lung, the number of macro-metastases was also significantly reduced for all treated groups by 55.4, 55.2 and 64.4%, respectively. The numbers of macro-metastases in the liver and kidneys were decreased under treatments, whereby a significant decrease could be only obtained for conjugate 2."	.
REF00075	PDC_00180	Breast cancer	Orthotopic 4T1 mice breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Number of macro-metastases decrease	64.40%	%	.	.	.	.	Breast cancer	4T1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	"The number of macro-metastases in peripheral organs, such as spleen, lung, liver and kidneys, was counted, in order to determine the anti-metastatic effect of free Dau and the GnRH-III conjugates on aggressive 4T1 BC orthotopic model (Figure 5A). The number of macro-metastases in spleen was significantly decreased in all treated groups (Dau,1and2) by 64.3, 72.8 and 78.1%. In the lung, the number of macro-metastases was also significantly reduced for all treated groups by 55.4, 55.2 and 64.4%, respectively. The numbers of macro-metastases in the liver and kidneys were decreased under treatments, whereby a significant decrease could be only obtained for conjugate2."	.
REF00075	PDC_00180	Breast cancer	Orthotopic 4T1 mice breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Micro-metastases decrease	49.40%	%	.	.	.	.	Breast cancer	4T1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	"The obtained data revealed that free Dau and both conjugates (1, 2) significantly inhibited the number of micro-metastases in the lung by 33.7, 43.8 and 49.4%, as compared to the control group. The proliferation index of lung metastases was significantly inhibited by 27.8, 37 and 39.1% in groups that were treated with free Dau, 1 and 2."	.
REF00075	PDC_00180	Breast cancer	Orthotopic 4T1 mice breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Proliferation index	39.10%	%	.	.	.	.	Breast cancer	4T1 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	"The obtained data revealed that free Dau and both conjugates (1, 2) significantly inhibited the number of micro-metastases in the lung by 33.7, 43.8 and 49.4%, as compared to the control group. The proliferation index of lung metastases was significantly inhibited by 27.8, 37 and 39.1% in groups that were treated with free Dau, 1 and 2."	.
REF00075	PDC_00180	Breast cancer	Orthotopic MDA-MB-231 human breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Body weigth change	8.20%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	15 mg/kg Dau content	.	"The body weight of the mice in control group was decreased by 2.7%, while in the groups treated with 1 and 2, it was decreased by 10.1 and 8.2%."	.
REF00075	PDC_00180	Breast cancer	Orthotopic MDA-MB-231 human breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor volume decrease	23.10%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	15 mg/kg Dau content	.	"Apart from that, a significant inhibition of the tumor volume was also obtained in groups which were treated with conjugate 1 (34.1%) and 2 (23.1%)."	.
REF00075	PDC_00180	Breast cancer	Orthotopic MDA-MB-231 human breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	23.10%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	15 mg/kg Dau content	.	"Apart from that, a significant inhibition of the tumor volume was also obtained in groups which were treated with conjugate 1 (34.1%) and 2 (23.1%)."	.
REF00075	PDC_00180	Breast cancer	Orthotopic MDA-MB-231 human breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor weight decrease	27.70%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	15 mg/kg Dau content	.	"Based on these tumor weights, we determined that free Dau, 1 and 2 inhibited tumor weight significantly by 40.1, 28.7 and 27.7% in the case of orthotopic human MDA-MB-231 breast tumor model."	.
REF00075	PDC_00180	Breast cancer	Orthotopic MDA-MB-231 human breast carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	27.70%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	15 mg/kg Dau content	.	"Based on these tumor weights, we determined that free Dau, 1 and 2 inhibited tumor weight significantly by 40.1, 28.7 and 27.7% in the case of orthotopic human MDA-MB-231 breast tumor model."	.
REF00075	PDC_00180	Colorectal cancer	Orthotopic HT-29 human colon carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor weight	87.10%	%	.	.	.	.	Colon adenocarcinoma	HT-29 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	"The obtained data reveal that Dau, 1 and 2 significantly inhibited the tumor growth, whereby the tumor weights were reduced by 84.3, 80.8 and 87.1%, as compared to the control group."	.
REF00075	PDC_00180	Colorectal cancer	Orthotopic HT-29 human colon carcinoma bearing mice model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	87.10%	%	.	.	.	.	Colon adenocarcinoma	HT-29 cell	.	"The cellular uptake of the conjugates was measured by flow cytometry on the tested cell lines. The obtained results displayed that the new conjugate 2 was taken up more efficiently than 1, with 1.7-2.7 times higher uptake rates, depending on the cell line (Figure 2D, Table S1). The normal cell line MRC-5, as well as PANC-1 cancer cell line showed two-fold lower uptake capacity in comparison to the other cancer cell lines."	.	10 mg/kg Dau content	.	"The obtained data reveal that Dau, 1 and 2 significantly inhibited the tumor growth, whereby the tumor weights were reduced by 84.3, 80.8 and 87.1%, as compared to the control group."	.
REF00066	PDC_00027	Inoperable or metastatic paragangliomas	.	Identified from the Human Clinical Data	.	Grade 3/4 subacute haematotoxicity	20%	%	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	Grade 3/4 subacute haematotoxicity occurred in 6 (20%) of patients. 	.
REF00066	PDC_00027	Inoperable or metastatic pheochromocytomas	.	Identified from the Human Clinical Data	.	Grade 3/4 subacute haematotoxicity	20%	%	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	Grade 3/4 subacute haematotoxicity occurred in 6 (20%) of patients. 	.
REF00066	PDC_00027	Inoperable or metastatic paragangliomas	.	Identified from the Human Clinical Data	.	Best tumour response	23%	%	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	Best tumour response was partial response in 7 (23%) and stable disease in 20 (67%)	.
REF00066	PDC_00027	Inoperable or metastatic pheochromocytomas	.	Identified from the Human Clinical Data	.	Best tumour response	23%	%	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	Best tumour response was partial response in 7 (23%) and stable disease in 20 (67%)	.
REF00066	PDC_00027	Inoperable or metastatic paragangliomas	.	Identified from the Human Clinical Data	.	Stable disease (SD)	67%	%	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	Best tumour response was partial response in 7 (23%) and stable disease in 20 (67%)	.
REF00066	PDC_00027	Inoperable or metastatic pheochromocytomas	.	Identified from the Human Clinical Data	.	Stable disease (SD)	67%	%	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	Best tumour response was partial response in 7 (23%) and stable disease in 20 (67%)	.
REF00066	PDC_00027	Inoperable or metastatic paragangliomas	.	Identified from the Human Clinical Data	.	Tumour inhibition rate	85%	%	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas with baseline disease progression.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	"In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs."	.
REF00066	PDC_00027	Inoperable or metastatic pheochromocytomas	.	Identified from the Human Clinical Data	.	Tumour inhibition rate	85%	%	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas with baseline disease progression.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	"In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs."	.
REF00066	PDC_00027	Inoperable or metastatic paragangliomas	.	Identified from the Human Clinical Data	.	Median progression-free survival (mPFS)	91 months	months	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas with parasympathetic paragangliomas.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	"In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs."	.
REF00066	PDC_00027	Inoperable or metastatic pheochromocytomas	.	Identified from the Human Clinical Data	.	Median progression-free survival (mPFS)	91 months	months	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas with parasympathetic paragangliomas.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	"In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs."	.
REF00066	PDC_00027	Inoperable or metastatic paragangliomas	.	Identified from the Human Clinical Data	.	Median progression-free survival (mPFS)	13 months	months	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas with sympathetic paragangliomas.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	"In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs."	.
REF00066	PDC_00027	Inoperable or metastatic pheochromocytomas	.	Identified from the Human Clinical Data	.	Median progression-free survival (mPFS)	13 months	months	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas with sympathetic paragangliomas.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	"In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs."	.
REF00066	PDC_00027	Inoperable or metastatic paragangliomas	.	Identified from the Human Clinical Data	.	Median progression-free survival (mPFS)	10 months	months	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas with metastatic pheochromocytomas.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	"In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs."	.
REF00066	PDC_00027	Inoperable or metastatic pheochromocytomas	.	Identified from the Human Clinical Data	.	Median progression-free survival (mPFS)	10 months	months	.	.	.	Patients with inoperable or metastatic paragangliomas and pheochromocytomas with metastatic pheochromocytomas.	.	.	.	.	Four cycles	7.4 Gb per cycle	.	"In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs."	.
REF00064	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Median overall survival (mOS)	50.7 months	months	.	.	.	Patients with neuroendocrine tumours who met selection criteria.	.	.	.	.	.	.	.	Estimated median overall survival was significantly longer for patients who met selection criteria compared with those who did not (50.7 vs 34.2 months) (P = 0.018).	.
REF00064	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Median overall survival (mOS)	34.2 months	months	.	.	.	Patients with neuroendocrine tumours who failed exclusion criteria.	.	.	.	.	.	.	.	Estimated median overall survival was significantly longer for patients who met selection criteria compared with those who did not (50.7 vs 34.2 months) (P = 0.018).	.
REF00064	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Haematological treatment-related serious adverse events	9.70%	%	.	.	.	Patients with neuroendocrine tumours.	.	.	.	.	.	.	.	"<sup>177</sup>Lu-DOTATATE was well tolerated with haematological, renal and hepatic treatment-related serious adverse events experienced by 9.7, 0.4 and 0.4% of patients respectively."	.
REF00064	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Treatment-emergent adverse event	0.40%	%	.	.	.	Patients with neuroendocrine tumours.	.	.	.	.	.	.	.	"<sup>177</sup>Lu-DOTATATE was well tolerated with haematological, renal and hepatic treatment-related serious adverse events experienced by 9.7, 0.4 and 0.4% of patients respectively."	.
REF00064	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Hepatic treatment-related serious adverse events	0.40%	%	.	.	.	Patients with neuroendocrine tumours.	.	.	.	.	.	.	.	"<sup>177</sup>Lu-DOTATATE was well tolerated with haematological, renal and hepatic treatment-related serious adverse events experienced by 9.7, 0.4 and 0.4% of patients respectively."	.
REF00074	PDC_00066	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	18.5 &plusmn; 3.77 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	"These results revealed that the cellular entry pathway of the BP9a-DOX conjugate was different from that of free DOX. The targeted intracellular uptake of the conjugate by HepG2 cells could possibly be related to TfR overexpressed there, whereas its scarce entry into L-O2 cells might be due to the absence of TfR, as illustrated in Figure 2."	.	.	CCK-8 assay	Its antiproliferative activity against HepG2 cells (IC50 18.5 &plusmn; 3.77 uM) was lower than that of free DOX.	.
REF00073	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Survival rate	83%	%	.	.	.	Patients with neuroendocrine tumor.	.	.	.	.	24 months	.	.	.	.
REF00073	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Median progression-free survival (mPFS)	40 months	months	.	.	.	Patients with neuroendocrine tumor.	.	.	.	.	.	.	.	.	.
REF00072	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Mortality rate	49.50%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	.	.
REF00072	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Median overall survival (mOS)	9.9 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	.	.
REF00061	PDC_00284	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	60%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	5 &micro;M	MTT assay	"Antiproliferative results showed that PTX1 inhibited cell proliferation by 18.7%. The anti-proliferative activity of CPT1 was diminished by 1.9-fold as compared to CPT whereas the activity of CPT2 was comparable to CPT, since CPT2 reduced the cell viability to 61%."	.
REF00061	PDC_00284	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	80%	%	.	.	.	.	Normal	HEK-298 cell	.	.	72 h	5 &micro;M	MTT assay	"The cytotoxicity of PTX and PTX1 was further evaluated in the normal human embryonic kidney cells (HEK-293) at 5 uM which showed reduced cell proliferation by ~34% and 18%, respectively, after 72 h using MTT assay, as shown in Figure 2. "	.
REF00061	PDC_00271	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	38%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	5 &micro;M	MTT assay	"Antiproliferative results showed that PTX1 inhibited cell proliferation by 18.7%. The anti-proliferative activity of CPT1 was diminished by 1.9-fold as compared to CPT whereas the activity of CPT2 was comparable to CPT, since CPT2 reduced the cell viability to 61%."	.
REF00061	PDC_00272	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	80%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	5 &micro;M	MTT assay	"Antiproliferative results showed that PTX1 inhibited cell proliferation by 18.7%. The anti-proliferative activity of CPT1 was diminished by 1.9-fold as compared to CPT whereas the activity of CPT2 was comparable to CPT, since CPT2 reduced the cell viability to 61%."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	102%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	2 h	10 nM	.	"The conjugate 13, peptide 9, and Dox showed no significant toxicity at or below 10 &mu;M, possibly due to the shorter incubation time of 2 h."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	74%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	2 h	100 nM	.	"The conjugate 13, peptide 9, and Dox showed no significant toxicity at or below 10 &mu;M, possibly due to the shorter incubation time of 2 h."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	75%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	2 h	1 &micro;M	.	"The conjugate 13, peptide 9, and Dox showed no significant toxicity at or below 10 &mu;M, possibly due to the shorter incubation time of 2 h."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	105%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	2 h	10 &micro;M	.	"The conjugate 13, peptide 9, and Dox showed no significant toxicity at or below 10 &mu;M, possibly due to the shorter incubation time of 2 h."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	98%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	2 h	100 &micro;M	.	"The conjugate 13, peptide 9, and Dox showed no significant toxicity at or below 10 &mu;M, possibly due to the shorter incubation time of 2 h."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	25%	%	.	.	.	.	Normal	RWPE-1 cell	.	.	72 h	5 &micro;M	MTS assay	"Dox conjugate 13 was moderately toxic with a reduced cell proliferation to a range of 25-35% as compared to Dox which reduced cell proliferation in the range of 20-34% for all selected four cell lines. However, it was interesting to observe that Doce conjugate 14 was almost nontoxic (cell proliferation within the range of 89-96%) in all the cell lines as compared to Doce alone which reduced the cell proliferation in the range of 54-61% (Figure 9)."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	38%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	72 h	5 &micro;M	MTS assay	"Dox conjugate 13 was moderately toxic with a reduced cell proliferation to a range of 25-35% as compared to Dox which reduced cell proliferation in the range of 20-34% for all selected four cell lines. However, it was interesting to observe that Doce conjugate 14 was almost nontoxic (cell proliferation within the range of 89-96%) in all the cell lines as compared to Doce alone which reduced the cell proliferation in the range of 54-61% (Figure 9)."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	22%	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	72 h	5 &micro;M	MTS assay	"Dox conjugate 13 was moderately toxic with a reduced cell proliferation to a range of 25-35% as compared to Dox which reduced cell proliferation in the range of 20-34% for all selected four cell lines. However, it was interesting to observe that Doce conjugate 14 was almost nontoxic (cell proliferation within the range of 89-96%) in all the cell lines as compared to Doce alone which reduced the cell proliferation in the range of 54-61% (Figure 9)."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	28%	%	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	72 h	5 &micro;M	MTS assay	"Dox conjugate 13 was moderately toxic with a reduced cell proliferation to a range of 25-35% as compared to Dox which reduced cell proliferation in the range of 20-34% for all selected four cell lines. However, it was interesting to observe that Doce conjugate 14 was almost nontoxic (cell proliferation within the range of 89-96%) in all the cell lines as compared to Doce alone which reduced the cell proliferation in the range of 54-61% (Figure 9)."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	108%	%	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	24 h	.	MTS assay	"An increase in the cytotoxicity of Dox and Dox/peptide 9 physical mixture as compared to the conjugate 13 over an incubation period of 24 h to 72 h. Conjugates 13 and 14 were found to be less cytotoxic as compared to drug alone in 24-72 h. These cells were not treated with TGF-, so very minimal or no overexpression of EDB-FN. Figure 10b showed the effect of overexpression of EDB-FN in the cell viability. There was no observed effect of TGF- treatment for the cytotoxicity of Dox and physical mixture of Dox/peptide 9 on the cell viability as compared to the TGF- untreated cell lines. However, conjugate 13 showed a decrease in cell viability by 17% after 72 h as compared to untreated cell lines. Similarly, Doce and Doce conjugate 14 showed decrease in cell viability by 16 and 10%, respectively, after 72 h. The physical mixtures of Doce/peptide 9 showed a decrease in cell viability by 16% as compared to untreated cells."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	78%	%	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	48 h	.	MTS assay	"An increase in the cytotoxicity of Dox and Dox/peptide 9 physical mixture as compared to the conjugate 13 over an incubation period of 24 h to 72 h. Conjugates 13 and 14 were found to be less cytotoxic as compared to drug alone in 24-72 h. These cells were not treated with TGF-, so very minimal or no overexpression of EDB-FN. Figure 10b showed the effect of overexpression of EDB-FN in the cell viability. There was no observed effect of TGF- treatment for the cytotoxicity of Dox and physical mixture of Dox/peptide 9 on the cell viability as compared to the TGF- untreated cell lines. However, conjugate 13 showed a decrease in cell viability by 17% after 72 h as compared to untreated cell lines. Similarly, Doce and Doce conjugate 14 showed decrease in cell viability by 16 and 10%, respectively, after 72 h. The physical mixtures of Doce/peptide 9 showed a decrease in cell viability by 16% as compared to untreated cells."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	70%	%	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	72 h	.	MTS assay	"An increase in the cytotoxicity of Dox and Dox/peptide 9 physical mixture as compared to the conjugate 13 over an incubation period of 24 h to 72 h. Conjugates 13 and 14 were found to be less cytotoxic as compared to drug alone in 24-72 h. These cells were not treated with TGF-, so very minimal or no overexpression of EDB-FN. Figure 10b showed the effect of overexpression of EDB-FN in the cell viability. There was no observed effect of TGF- treatment for the cytotoxicity of Dox and physical mixture of Dox/peptide 9 on the cell viability as compared to the TGF- untreated cell lines. However, conjugate 13 showed a decrease in cell viability by 17% after 72 h as compared to untreated cell lines. Similarly, Doce and Doce conjugate 14 showed decrease in cell viability by 16 and 10%, respectively, after 72 h. The physical mixtures of Doce/peptide 9 showed a decrease in cell viability by 16% as compared to untreated cells."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	110%	%	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	24 h	.	MTS assay	"An increase in the cytotoxicity of Dox and Dox/peptide 9 physical mixture as compared to the conjugate 13 over an incubation period of 24 h to 72 h. Conjugates 13 and 14 were found to be less cytotoxic as compared to drug alone in 24-72 h. These cells were not treated with TGF-, so very minimal or no overexpression of EDB-FN. Figure 10b showed the effect of overexpression of EDB-FN in the cell viability. There was no observed effect of TGF- treatment for the cytotoxicity of Dox and physical mixture of Dox/peptide 9 on the cell viability as compared to the TGF- untreated cell lines. However, conjugate 13 showed a decrease in cell viability by 17% after 72 h as compared to untreated cell lines. Similarly, Doce and Doce conjugate 14 showed decrease in cell viability by 16 and 10%, respectively, after 72 h. The physical mixtures of Doce/peptide 9 showed a decrease in cell viability by 16% as compared to untreated cells."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	77%	%	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	48 h	.	MTS assay	"An increase in the cytotoxicity of Dox and Dox/peptide 9 physical mixture as compared to the conjugate 13 over an incubation period of 24 h to 72 h. Conjugates 13 and 14 were found to be less cytotoxic as compared to drug alone in 24-72 h. These cells were not treated with TGF-, so very minimal or no overexpression of EDB-FN. Figure 10b showed the effect of overexpression of EDB-FN in the cell viability. There was no observed effect of TGF- treatment for the cytotoxicity of Dox and physical mixture of Dox/peptide 9 on the cell viability as compared to the TGF- untreated cell lines. However, conjugate 13 showed a decrease in cell viability by 17% after 72 h as compared to untreated cell lines. Similarly, Doce and Doce conjugate 14 showed decrease in cell viability by 16 and 10%, respectively, after 72 h. The physical mixtures of Doce/peptide 9 showed a decrease in cell viability by 16% as compared to untreated cells."	.
REF00070	PDC_00142	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	48%	%	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	72 h	.	MTS assay	"An increase in the cytotoxicity of Dox and Dox/peptide 9 physical mixture as compared to the conjugate 13 over an incubation period of 24 h to 72 h. Conjugates 13 and 14 were found to be less cytotoxic as compared to drug alone in 24-72 h. These cells were not treated with TGF-, so very minimal or no overexpression of EDB-FN. Figure 10b showed the effect of overexpression of EDB-FN in the cell viability. There was no observed effect of TGF- treatment for the cytotoxicity of Dox and physical mixture of Dox/peptide 9 on the cell viability as compared to the TGF- untreated cell lines. However, conjugate 13 showed a decrease in cell viability by 17% after 72 h as compared to untreated cell lines. Similarly, Doce and Doce conjugate 14 showed decrease in cell viability by 16 and 10%, respectively, after 72 h. The physical mixtures of Doce/peptide 9 showed a decrease in cell viability by 16% as compared to untreated cells."	.
REF00070	PDC_00132	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	95%	%	.	.	.	.	Normal	RWPE-1 cell	.	.	72 h	5 &micro;M	MTS assay	"Dox conjugate 13 was moderately toxic with a reduced cell proliferation to a range of 25-35% as compared to Dox which reduced cell proliferation in the range of 20-34% for all selected four cell lines. However, it was interesting to observe that Doce conjugate 14 was almost nontoxic (cell proliferation within the range of 89-96%) in all the cell lines as compared to Doce alone which reduced the cell proliferation in the range of 54-61% (Figure 9)."	.
REF00070	PDC_00132	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	98%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	72 h	5 &micro;M	MTS assay	"Dox conjugate 13 was moderately toxic with a reduced cell proliferation to a range of 25-35% as compared to Dox which reduced cell proliferation in the range of 20-34% for all selected four cell lines. However, it was interesting to observe that Doce conjugate 14 was almost nontoxic (cell proliferation within the range of 89-96%) in all the cell lines as compared to Doce alone which reduced the cell proliferation in the range of 54-61% (Figure 9)."	.
REF00070	PDC_00132	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	96%	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	72 h	5 &micro;M	MTS assay	"Dox conjugate 13 was moderately toxic with a reduced cell proliferation to a range of 25-35% as compared to Dox which reduced cell proliferation in the range of 20-34% for all selected four cell lines. However, it was interesting to observe that Doce conjugate 14 was almost nontoxic (cell proliferation within the range of 89-96%) in all the cell lines as compared to Doce alone which reduced the cell proliferation in the range of 54-61% (Figure 9)."	.
REF00070	PDC_00132	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	99%	%	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	72 h	5 &micro;M	MTS assay	"Dox conjugate 13 was moderately toxic with a reduced cell proliferation to a range of 25-35% as compared to Dox which reduced cell proliferation in the range of 20-34% for all selected four cell lines. However, it was interesting to observe that Doce conjugate 14 was almost nontoxic (cell proliferation within the range of 89-96%) in all the cell lines as compared to Doce alone which reduced the cell proliferation in the range of 54-61% (Figure 9)."	.
REF00070	PDC_00132	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	100%	%	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	24 h	.	MTS assay	"An increase in the cytotoxicity of Dox and Dox/peptide 9 physical mixture as compared to the conjugate 13 over an incubation period of 24 h to 72 h. Conjugates 13 and 14 were found to be less cytotoxic as compared to drug alone in 24-72 h. These cells were not treated with TGF-, so very minimal or no overexpression of EDB-FN. Figure 10b showed the effect of overexpression of EDB-FN in the cell viability. There was no observed effect of TGF- treatment for the cytotoxicity of Dox and physical mixture of Dox/peptide 9 on the cell viability as compared to the TGF- untreated cell lines. However, conjugate 13 showed a decrease in cell viability by 17% after 72 h as compared to untreated cell lines. Similarly, Doce and Doce conjugate 14 showed decrease in cell viability by 16 and 10%, respectively, after 72 h. The physical mixtures of Doce/peptide 9 showed a decrease in cell viability by 16% as compared to untreated cells."	.
REF00070	PDC_00132	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	78%	%	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	48 h	.	MTS assay	"An increase in the cytotoxicity of Dox and Dox/peptide 9 physical mixture as compared to the conjugate 13 over an incubation period of 24 h to 72 h. Conjugates 13 and 14 were found to be less cytotoxic as compared to drug alone in 24-72 h. These cells were not treated with TGF-, so very minimal or no overexpression of EDB-FN. Figure 10b showed the effect of overexpression of EDB-FN in the cell viability. There was no observed effect of TGF- treatment for the cytotoxicity of Dox and physical mixture of Dox/peptide 9 on the cell viability as compared to the TGF- untreated cell lines. However, conjugate 13 showed a decrease in cell viability by 17% after 72 h as compared to untreated cell lines. Similarly, Doce and Doce conjugate 14 showed decrease in cell viability by 16 and 10%, respectively, after 72 h. The physical mixtures of Doce/peptide 9 showed a decrease in cell viability by 16% as compared to untreated cells."	.
REF00070	PDC_00132	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	55%	%	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	72 h	.	MTS assay	"An increase in the cytotoxicity of Dox and Dox/peptide 9 physical mixture as compared to the conjugate 13 over an incubation period of 24 h to 72 h. Conjugates 13 and 14 were found to be less cytotoxic as compared to drug alone in 24-72 h. These cells were not treated with TGF-, so very minimal or no overexpression of EDB-FN. Figure 10b showed the effect of overexpression of EDB-FN in the cell viability. There was no observed effect of TGF- treatment for the cytotoxicity of Dox and physical mixture of Dox/peptide 9 on the cell viability as compared to the TGF- untreated cell lines. However, conjugate 13 showed a decrease in cell viability by 17% after 72 h as compared to untreated cell lines. Similarly, Doce and Doce conjugate 14 showed decrease in cell viability by 16 and 10%, respectively, after 72 h. The physical mixtures of Doce/peptide 9 showed a decrease in cell viability by 16% as compared to untreated cells."	.
REF00070	PDC_00132	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	95%	%	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	24 h	.	MTS assay	"An increase in the cytotoxicity of Dox and Dox/peptide 9 physical mixture as compared to the conjugate 13 over an incubation period of 24 h to 72 h. Conjugates 13 and 14 were found to be less cytotoxic as compared to drug alone in 24-72 h. These cells were not treated with TGF-, so very minimal or no overexpression of EDB-FN. Figure 10b showed the effect of overexpression of EDB-FN in the cell viability. There was no observed effect of TGF- treatment for the cytotoxicity of Dox and physical mixture of Dox/peptide 9 on the cell viability as compared to the TGF- untreated cell lines. However, conjugate 13 showed a decrease in cell viability by 17% after 72 h as compared to untreated cell lines. Similarly, Doce and Doce conjugate 14 showed decrease in cell viability by 16 and 10%, respectively, after 72 h. The physical mixtures of Doce/peptide 9 showed a decrease in cell viability by 16% as compared to untreated cells."	.
REF00070	PDC_00132	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	80%	%	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	48 h	.	MTS assay	"An increase in the cytotoxicity of Dox and Dox/peptide 9 physical mixture as compared to the conjugate 13 over an incubation period of 24 h to 72 h. Conjugates 13 and 14 were found to be less cytotoxic as compared to drug alone in 24-72 h. These cells were not treated with TGF-, so very minimal or no overexpression of EDB-FN. Figure 10b showed the effect of overexpression of EDB-FN in the cell viability. There was no observed effect of TGF- treatment for the cytotoxicity of Dox and physical mixture of Dox/peptide 9 on the cell viability as compared to the TGF- untreated cell lines. However, conjugate 13 showed a decrease in cell viability by 17% after 72 h as compared to untreated cell lines. Similarly, Doce and Doce conjugate 14 showed decrease in cell viability by 16 and 10%, respectively, after 72 h. The physical mixtures of Doce/peptide 9 showed a decrease in cell viability by 16% as compared to untreated cells."	.
REF00070	PDC_00132	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	45%	%	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	72 h	.	.	.	.
REF00057	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	10.7 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer; taxane chemotherapy pretreated.	.	.	.	.	.	.	.	.	.
REF00057	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median radiographic progression-free survival (rPFS)	6.0 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer; taxane chemotherapy pretreated.	.	.	.	.	.	.	.	.	.
REF00057	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	40.00%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer; taxane chemotherapy pretreated.	.	.	.	.	.	.	.	.	.
REF00057	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	27.1 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer; naive (T-naive).	.	.	.	.	.	.	.	.	.
REF00057	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median radiographic progression-free survival (rPFS)	8.8 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer; naive (T-naive).	.	.	.	.	.	.	.	.	.
REF00057	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	57.00%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer; naive (T-naive).	.	.	.	.	.	.	.	.	.
REF00056	PDC_00352	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	452 &plusmn; 60 nM	nM	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"As shown in Table 1, the cytotoxic potency of the tubugi-1-SH was - in case of HT-29 and PC-3 - by factors 5 to 8 higher compared to the entire peptide-toxin conjugate 8. The only slight increase of cytotoxic activity of compound 9 compared to the complete conjugate 8 in Colo320 cells is most likely caused by a generally weak responsiveness of Colo320 cells towards tubugi-1-SH and the entire conjugate tubugi-1-SS-NPY. When compared with HT-29 and PC-3 cells, the IC50 value of tubugi-1-SH is by factor 10 higher in Colo320. Since the membrane passage of tubugi-1-SH is not depending on a NPY receptor, there have to be other explanations for the reduced cytotoxic impact of tubugi-1 and corresponding derivatives in Colo320, rather than the NPY Y1 receptor expression level."	.
REF00056	PDC_00352	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	205 &plusmn; 49 nM	nM	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"As shown in Table 1, the cytotoxic potency of the tubugi-1-SH was - in case of HT-29 and PC-3 - by factors 5 to 8 higher compared to the entire peptide-toxin conjugate 8. The only slight increase of cytotoxic activity of compound 9 compared to the complete conjugate 8 in Colo320 cells is most likely caused by a generally weak responsiveness of Colo320 cells towards tubugi-1-SH and the entire conjugate tubugi-1-SS-NPY. When compared with HT-29 and PC-3 cells, the IC50 value of tubugi-1-SH is by factor 10 higher in Colo320. Since the membrane passage of tubugi-1-SH is not depending on a NPY receptor, there have to be other explanations for the reduced cytotoxic impact of tubugi-1 and corresponding derivatives in Colo320, rather than the NPY Y1 receptor expression level."	.
REF00056	PDC_00352	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	706 &plusmn; 185 nM	nM	.	.	.	.	Colon adenocarcinoma	COLO 320 cell	.	.	.	.	.	"As shown in Table 1, the cytotoxic potency of the tubugi-1-SH was - in case of HT-29 and PC-3 - by factors 5 to 8 higher compared to the entire peptide-toxin conjugate 8. The only slight increase of cytotoxic activity of compound 9 compared to the complete conjugate 8 in Colo320 cells is most likely caused by a generally weak responsiveness of Colo320 cells towards tubugi-1-SH and the entire conjugate tubugi-1-SS-NPY. When compared with HT-29 and PC-3 cells, the IC50 value of tubugi-1-SH is by factor 10 higher in Colo320. Since the membrane passage of tubugi-1-SH is not depending on a NPY receptor, there have to be other explanations for the reduced cytotoxic impact of tubugi-1 and corresponding derivatives in Colo320, rather than the NPY Y1 receptor expression level."	.
REF00056	PDC_00352	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	2%	%	.	.	.	.	Askin tumor 	SK-N-MC cell	.	.	6 h	10 &micro;M	.	"The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines. "	.
REF00056	PDC_00352	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	10%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	6 h	10 &micro;M	.	"The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines. "	.
REF00056	PDC_00352	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	35%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	6 h	10 &micro;M	.	"The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines. "	.
REF00056	PDC_00352	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	50%	%	.	.	.	.	Normal	Normal mammary gland epithelium	.	.	6 h	10 &micro;M	.	"The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines. "	.
REF00056	PDC_00352	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	0%	%	.	.	.	.	Askin tumor 	SK-N-MC cell	.	.	72 h	10 &micro;M	.	"The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines. "	.
REF00056	PDC_00352	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	5%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	72 h	10 &micro;M	.	"The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines. "	.
REF00056	PDC_00352	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	20%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	72 h	10 &micro;M	.	"The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines. "	.
REF00056	PDC_00352	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	20%	%	.	.	.	.	Normal	Normal mammary gland epithelium	.	.	72 h	10 &micro;M	.	"The 72 h treatment is more effective than the 6 h pulse treatment. Notably, in vitro antitumor activities of 8 were found to correlate very good with the hY1R expression levels, as detected by gene expression analyses using RT-qPCR. Both the cytotoxic activity and the hY1R expression level rank in the order SK-N-MC > MDA-MB-468 > MDA-MB-231 > 184B5, what proofs the hY1R-specific and -selective nature of the mode of antitumor action of the designed PDC 8. Importantly, the activity of 8 against the selected normal breast cell line 184B5 is in the same order of magnitude as for the hY1R-deficient tumor cell line (MDA-MB-231), both tested at even higher concentration of the PDC than for the Y1 cell lines. "	.
REF00055	PDC_00042	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Decrease of median PSA level	44%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"After RLT the median PSA level decreased by 44%, TTV by 45.1%, SUVmean by 25.8% and RECIST by 11.3%. "	.
REF00055	PDC_00042	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Decrease of total tumor volumes (TTV)	45%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"After RLT the median PSA level decreased by 44%, TTV by 45.1%, SUVmean by 25.8% and RECIST by 11.3%. "	.
REF00055	PDC_00042	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Mean standardized uptake values (SUV<sub>mean</sub>)	26%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"After RLT the median PSA level decreased by 44%, TTV by 45.1%, SUVmean by 25.8% and RECIST by 11.3%. "	.
REF00055	PDC_00042	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Response Evaluation Criteria in Solid Tumours (RECIST)	11.30%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"After RLT the median PSA level decreased by 44%, TTV by 45.1%, SUVmean by 25.8% and RECIST by 11.3%. "	.
REF00055	PDC_00042	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	PSA response	47.40%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A PSA response was seen in 18 patients (47.4%), stable disease in 12 (31.6%) and progressive disease in 8 (21.1%). "	.
REF00055	PDC_00042	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Stable disease (SD)	31.60%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A PSA response was seen in 18 patients (47.4%), stable disease in 12 (31.6%) and progressive disease in 8 (21.1%). "	.
REF00055	PDC_00042	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Progressive Disease (PD)	21.10%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A PSA response was seen in 18 patients (47.4%), stable disease in 12 (31.6%) and progressive disease in 8 (21.1%). "	.
REF00054	PDC_00027	Functioning pancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 3/4 subacute hematological toxicity	12%	%	.	.	.	Patients with functioning pancreatic neuroendocrine tumors.	.	.	.	.	4 cycles	7.4 GBq/cycle	.	"Subacute hematological toxicity, grade 3 or 4 occurred in 4 patients (12%) and a hormonal crisis in 3 patients (9%). PRRT resulted in partial or complete response in 59% of patients and the disease control rate was 78% in patients with baseline progression. 71% of patients with uncontrolled symptoms had a reduction of symptoms and a more than 80% decrease of circulating hormone levels was measured during follow-up. After PRRT, median progression-free survival was 18.1 months (interquartile range: 3.3 to 35.7) with a concurrent increase in QOL."	.
REF00054	PDC_00027	Functioning pancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Hormonal crisis	9%	%	.	.	.	Patients with functioning pancreatic neuroendocrine tumors.	.	.	.	.	4 cycles	7.4 GBq/cycle	.	"Subacute hematological toxicity, grade 3 or 4 occurred in 4 patients (12%) and a hormonal crisis in 3 patients (9%). PRRT resulted in partial or complete response in 59% of patients and the disease control rate was 78% in patients with baseline progression. 71% of patients with uncontrolled symptoms had a reduction of symptoms and a more than 80% decrease of circulating hormone levels was measured during follow-up. After PRRT, median progression-free survival was 18.1 months (interquartile range: 3.3 to 35.7) with a concurrent increase in QOL."	.
REF00054	PDC_00027	Functioning pancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)/complete response (CP)	59%	%	.	.	.	Patients with functioning pancreatic neuroendocrine tumors.	.	.	.	.	4 cycles	7.4 GBq/cycle	.	"Subacute hematological toxicity, grade 3 or 4 occurred in 4 patients (12%) and a hormonal crisis in 3 patients (9%). PRRT resulted in partial or complete response in 59% of patients and the disease control rate was 78% in patients with baseline progression. 71% of patients with uncontrolled symptoms had a reduction of symptoms and a more than 80% decrease of circulating hormone levels was measured during follow-up. After PRRT, median progression-free survival was 18.1 months (interquartile range: 3.3 to 35.7) with a concurrent increase in QOL."	.
REF00054	PDC_00027	Functioning pancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	78%	%	.	.	.	Patients with functioning pancreatic neuroendocrine tumors.	.	.	.	.	4 cycles	7.4 GBq/cycle	.	"Subacute hematological toxicity, grade 3 or 4 occurred in 4 patients (12%) and a hormonal crisis in 3 patients (9%). PRRT resulted in partial or complete response in 59% of patients and the disease control rate was 78% in patients with baseline progression. 71% of patients with uncontrolled symptoms had a reduction of symptoms and a more than 80% decrease of circulating hormone levels was measured during follow-up. After PRRT, median progression-free survival was 18.1 months (interquartile range: 3.3 to 35.7) with a concurrent increase in QOL."	.
REF00053	PDC_00096	Tumor	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	28.9 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	"As shown in Figure 3, the FITC-loaded CRB-FFE-YSV hydrogel (hydrogel/FITC) displayed much stronger green fluorescence than that of free FITC in HepG2 cells, indicating that the formation of nanofibers (CRB-FFE-YSV) could greatly improve the cellular uptake of drugs. We then further compared the concentration of YSV and CRB-FFE-YSV in the different cancer cell models (HepG2 cells, MCF-7 cells, and BEL-7402 cells) after 4 h incubation. The results in Figure 4 showed that the concentration of CRB-FFE-YSV in all above cell lines was approximately 2-3-fold higher than the intracellular concentration of free YSV. "	48 h	.	MTT assay	"The corresponding IC50 values of CRB-FFE-YSV nanofibers against HepG2, MCF-7, and BEL-7402 cells were 28.9, 47.5, and 25.7 um, respectively, which were much lower than that of free YSV (842.9, 999.5, and 719.2 um), free CRB (154.4, 214.6, and 192.5 um), and the mixed drugs (150.0, 190.3, and 180.6 um). "	.
REF00053	PDC_00096	Tumor	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	47.5 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"As shown in Figure 3, the FITC-loaded CRB-FFE-YSV hydrogel (hydrogel/FITC) displayed much stronger green fluorescence than that of free FITC in HepG2 cells, indicating that the formation of nanofibers (CRB-FFE-YSV) could greatly improve the cellular uptake of drugs. We then further compared the concentration of YSV and CRB-FFE-YSV in the different cancer cell models (HepG2 cells, MCF-7 cells, and BEL-7402 cells) after 4 h incubation. The results in Figure 4 showed that the concentration of CRB-FFE-YSV in all above cell lines was approximately 2-3-fold higher than the intracellular concentration of free YSV. "	48 h	.	MTT assay	"The corresponding IC50 values of CRB-FFE-YSV nanofibers against HepG2, MCF-7, and BEL-7402 cells were 28.9, 47.5, and 25.7 um, respectively, which were much lower than that of free YSV (842.9, 999.5, and 719.2 um), free CRB (154.4, 214.6, and 192.5 um), and the mixed drugs (150.0, 190.3, and 180.6 um). "	.
REF00053	PDC_00096	Tumor	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	25.7 &micro;M	&micro;M	.	.	.	.	Hepatoma	Bel-7402 cell	.	"As shown in Figure 3, the FITC-loaded CRB-FFE-YSV hydrogel (hydrogel/FITC) displayed much stronger green fluorescence than that of free FITC in HepG2 cells, indicating that the formation of nanofibers (CRB-FFE-YSV) could greatly improve the cellular uptake of drugs. We then further compared the concentration of YSV and CRB-FFE-YSV in the different cancer cell models (HepG2 cells, MCF-7 cells, and BEL-7402 cells) after 4 h incubation. The results in Figure 4 showed that the concentration of CRB-FFE-YSV in all above cell lines was approximately 2-3-fold higher than the intracellular concentration of free YSV. "	48 h	.	MTT assay	"The corresponding IC50 values of CRB-FFE-YSV nanofibers against HepG2, MCF-7, and BEL-7402 cells were 28.9, 47.5, and 25.7 um, respectively, which were much lower than that of free YSV (842.9, 999.5, and 719.2 um), free CRB (154.4, 214.6, and 192.5 um), and the mixed drugs (150.0, 190.3, and 180.6 um). "	.
REF00053	PDC_00096	Tumor	HepG2-tumor-bearing BALB/c nude mice.	Discovered Using Cell Line-derived Xenograft Model	.	Relative tumor volume of mice	356%	%	.	.	.	.	Hepatoblastoma	GPC3 positive HepG2 cell	.	"As shown in Figure 3, the FITC-loaded CRB-FFE-YSV hydrogel (hydrogel/FITC) displayed much stronger green fluorescence than that of free FITC in HepG2 cells, indicating that the formation of nanofibers (CRB-FFE-YSV) could greatly improve the cellular uptake of drugs. We then further compared the concentration of YSV and CRB-FFE-YSV in the different cancer cell models (HepG2 cells, MCF-7 cells, and BEL-7402 cells) after 4 h incubation. The results in Figure 4 showed that the concentration of CRB-FFE-YSV in all above cell lines was approximately 2-3-fold higher than the intracellular concentration of free YSV. "	"Day 1, day 4, day 7, and day 10"	10 &micro;mol/kg	.	"After treatment for 28 days, the final relative tumor volume of mice treated with PBS, YSV, CRB, YSV + CRB, or CRB-FFE-YSV hydrogel was 927, 728, 491, 514, and 356%, respectively. "	.
REF00052	PDC_00351	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	17%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	"As shown in Figure 1b, free DOX emitted bright red fluorescence in both HepG2 and HEK293 cells, demonstrating its nonselective uptake by cancer and normal cells. The fluorescence signal was localized to cell nucleus by costaining with nucleus indicator Hoechst (Figure 2a and Figure S-10). In contrast, PDC shows a significant difference in both cellular uptake and subcellular distribution. Red fluorescence only can be detected in cancerous HepG2 cells while HEK293 cells remained dark after the same treatment (Figure 1b), suggesting the high specificity of PDC for cancer cell recognition and internalization. "	48 h	20 &micro;M	MTT assay	PDC killed most HepG2 cells with a high efficiency of 83% and left HEK293 cells unaffected.	"Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant"
REF00052	PDC_00351	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	40%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"As shown in Figure 1b, free DOX emitted bright red fluorescence in both HepG2 and HEK293 cells, demonstrating its nonselective uptake by cancer and normal cells. The fluorescence signal was localized to cell nucleus by costaining with nucleus indicator Hoechst (Figure 2a and Figure S-10). In contrast, PDC shows a significant difference in both cellular uptake and subcellular distribution. Red fluorescence only can be detected in cancerous HepG2 cells while HEK293 cells remained dark after the same treatment (Figure 1b), suggesting the high specificity of PDC for cancer cell recognition and internalization. "	48 h	20 &micro;M	MTT assay	PDC maintained almost the same cytotoxicity against MCF-7/ADR cells and MCF-7/WT cells 	"Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant"
REF00052	PDC_00351	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	45%	%	.	.	.	.	Invasive breast carcinoma	MCF7/ADR cell	.	"As shown in Figure 1b, free DOX emitted bright red fluorescence in both HepG2 and HEK293 cells, demonstrating its nonselective uptake by cancer and normal cells. The fluorescence signal was localized to cell nucleus by costaining with nucleus indicator Hoechst (Figure 2a and Figure S-10). In contrast, PDC shows a significant difference in both cellular uptake and subcellular distribution. Red fluorescence only can be detected in cancerous HepG2 cells while HEK293 cells remained dark after the same treatment (Figure 1b), suggesting the high specificity of PDC for cancer cell recognition and internalization. "	48 h	20 &micro;M	MTT assay	PDC maintained almost the same cytotoxicity against MCF-7/ADR cells and MCF-7/WT cells 	"Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant"
REF00052	PDC_00351	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	100%	%	.	.	.	.	Normal	HEK293 cell	.	"As shown in Figure 1b, free DOX emitted bright red fluorescence in both HepG2 and HEK293 cells, demonstrating its nonselective uptake by cancer and normal cells. The fluorescence signal was localized to cell nucleus by costaining with nucleus indicator Hoechst (Figure 2a and Figure S-10). In contrast, PDC shows a significant difference in both cellular uptake and subcellular distribution. Red fluorescence only can be detected in cancerous HepG2 cells while HEK293 cells remained dark after the same treatment (Figure 1b), suggesting the high specificity of PDC for cancer cell recognition and internalization. "	48 h	20 &micro;M	MTT assay	PDC killed most HepG2 cells with a high efficiency of 83% and left HEK293 cells unaffected.	"Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant"
REF00052	PDC_00351	Tumor	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	15 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"As shown in Figure 1b, free DOX emitted bright red fluorescence in both HepG2 and HEK293 cells, demonstrating its nonselective uptake by cancer and normal cells. The fluorescence signal was localized to cell nucleus by costaining with nucleus indicator Hoechst (Figure 2a and Figure S-10). In contrast, PDC shows a significant difference in both cellular uptake and subcellular distribution. Red fluorescence only can be detected in cancerous HepG2 cells while HEK293 cells remained dark after the same treatment (Figure 1b), suggesting the high specificity of PDC for cancer cell recognition and internalization. "	.	.	.	"For PDC, its IC50 values against MCF-7/WT (15 uM) and MCF-7/ADR (18 uM) are almost the same, confirming its effectiveness in bypass drug resistance."	"Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant"
REF00052	PDC_00351	Tumor	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	18 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF7/ADR cell	.	"As shown in Figure 1b, free DOX emitted bright red fluorescence in both HepG2 and HEK293 cells, demonstrating its nonselective uptake by cancer and normal cells. The fluorescence signal was localized to cell nucleus by costaining with nucleus indicator Hoechst (Figure 2a and Figure S-10). In contrast, PDC shows a significant difference in both cellular uptake and subcellular distribution. Red fluorescence only can be detected in cancerous HepG2 cells while HEK293 cells remained dark after the same treatment (Figure 1b), suggesting the high specificity of PDC for cancer cell recognition and internalization. "	.	.	.	"For PDC, its IC50 values against MCF-7/WT (15 uM) and MCF-7/ADR (18 uM) are almost the same, confirming its effectiveness in bypass drug resistance."	"Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant"
REF00052	PDC_00351	Tumor	HepG2 tumor xenograft model.	Discovered Using Cell Line-derived Xenograft Model	.	Average tumor volume shrunk	55%	%	.	.	.	.	.	.	.	"As shown in Figure 1b, free DOX emitted bright red fluorescence in both HepG2 and HEK293 cells, demonstrating its nonselective uptake by cancer and normal cells. The fluorescence signal was localized to cell nucleus by costaining with nucleus indicator Hoechst (Figure 2a and Figure S-10). In contrast, PDC shows a significant difference in both cellular uptake and subcellular distribution. Red fluorescence only can be detected in cancerous HepG2 cells while HEK293 cells remained dark after the same treatment (Figure 1b), suggesting the high specificity of PDC for cancer cell recognition and internalization. "	18 days	20 &micro;M	.	The average tumor volume shrunk by 55% at day 18 compared with that of the control group (Figure 4c). 	"Initiated by the interaction between AP2H and membrane-anchored LAPTM4B protein, PDC specifically recognized and bound cancer cells. The receptor-mediated endocytic pathway then led to the delivery of PDC to lysosomes. The low pH environment in lysosomes efficiently cut the hydrazone bond and released TPP-DOX. The successful escape from lysosomes enabled further transportation of TPP-DOX to mitochondria directed by targeting group TPP. Because TPP-DOX is highly active in producing ROS and mitochondria are prone to oxidative damage, the disruption in the electron transport chain and ATP synthesis finally lead to mitochondrial dysfunction and cell death. With dual-targeting ability, PDC can effectively bypass the interaction with P-gp. Meanwhile, due to the energy-dependent expression feature of P-gp, the damage to mitochondria inhibit P-gp expression, thus inhibit the efflux. (9) The targeted and mitochondria interrupted cell damaging pathway allow PDC to exert toxicity both wild type and drug resistant"
REF00051	PDC_00080	Tumor	EDB-positive human glioblastoma-bearing mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Anti-tumor activity	23.90%	%	.	.	.	.	.	.	2.01 h	.	6 days	Equivalent to 2 mg SN38/kg	.	In situ HC[cot-APTEDB-SN38/Abcot] at an SN38/kg dose-equivalent of 2 mg effectively suppressed tumor growth and showed much greater antitumor activity (49.8% inhibition) than both cot-APTEDB-SN38 alone (23.9% inhibition) and CPT-11 (10.6% inhibition).	.
REF00050	PDC_00028	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Median progression-free survival (mPFS)	4.1 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6-8 weekly; 6 cycle	7.4 GBq	.	"Prostate-specific antigen decline of &ge;50% was achieved in 38 patients, median clinical progression-free survival (cPFS) was 4.1 mouth, and median overall survival (OS) was 12.9 mouth. "	.
REF00050	PDC_00028	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Median overall survival (mOS)	12.9 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6-8 weekly; 6 cycle	7.4 GBq	.	"Prostate-specific antigen decline of &ge;50% was achieved in 38 patients, median clinical progression-free survival (cPFS) was 4.1 mouth, and median overall survival (OS) was 12.9 mouth. "	.
REF00050	PDC_00028	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Grade 3/4 anemia	9%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6-8 weekly; 6 cycle	7.4 GBq	.	"Treatment-emergent hematologic grade 3/4 toxicities were anemia (9%), thrombocytopenia (4%), and neutropenia (6%). "	.
REF00050	PDC_00028	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Grade 3/4 thrombocytopenia	4%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6-8 weekly; 6 cycle	7.4 GBq	.	"Treatment-emergent hematologic grade 3/4 toxicities were anemia (9%), thrombocytopenia (4%), and neutropenia (6%). "	.
REF00050	PDC_00028	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Grade 3/4 neutropenia	6%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6-8 weekly; 6 cycle	7.4 GBq	.	"Treatment-emergent hematologic grade 3/4 toxicities were anemia (9%), thrombocytopenia (4%), and neutropenia (6%). "	.
REF00049	PDC_00020	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	55%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	4.67 h	.	48 h	25 &micro;M	MTT assay	"The results showed that all the conjugates had lower antiproliferative effects than Dox at the tested concentrations (Figure 2A); this may be related to inefficient release of Dox from the conjugate caused by the relative stable thioether bond linkage between Dox-SMP and GnRH analog. The antiproliferative effects of the three conjugates were close at 25, 50, and 75 uM. While at 100 uM, conjugate II exhibited higher inhibitory effect than that of I and III. "	.
REF00049	PDC_00020	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	50%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	4.67 h	.	48 h	50 &micro;M	MTT assay	"The results showed that all the conjugates had lower antiproliferative effects than Dox at the tested concentrations (Figure 2A); this may be related to inefficient release of Dox from the conjugate caused by the relative stable thioether bond linkage between Dox-SMP and GnRH analog. The antiproliferative effects of the three conjugates were close at 25, 50, and 75 uM. While at 100 uM, conjugate II exhibited higher inhibitory effect than that of I and III. "	.
REF00049	PDC_00020	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	38%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	4.67 h	.	48 h	75 &micro;M	MTT assay	"The results showed that all the conjugates had lower antiproliferative effects than Dox at the tested concentrations (Figure 2A); this may be related to inefficient release of Dox from the conjugate caused by the relative stable thioether bond linkage between Dox-SMP and GnRH analog. The antiproliferative effects of the three conjugates were close at 25, 50, and 75 uM. While at 100 uM, conjugate II exhibited higher inhibitory effect than that of I and III. "	"lthough RNT with <sup>177</sup>Lu-DOTATATE/PSMA is known as a novel and effective therapy option for cancer that significantly improves the quality of life and survival of patients, it may have acute or chronic side effects. Therefore, any method that can ameliorate these side effects is useful in the RNT process. For this purpose, a few clinical studies have reported that antioxidants as free radical scavengers such as amifostine and vitamins C and E can reduce radioiodine-related side effects, particularly in salivary glands in thyroid cancer patients."
REF00049	PDC_00020	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	30%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	4.67 h	.	48 h	100 &micro;M	MTT assay	"The results showed that all the conjugates had lower antiproliferative effects than Dox at the tested concentrations (Figure 2A); this may be related to inefficient release of Dox from the conjugate caused by the relative stable thioether bond linkage between Dox-SMP and GnRH analog. The antiproliferative effects of the three conjugates were close at 25, 50, and 75 uM. While at 100 uM, conjugate II exhibited higher inhibitory effect than that of I and III. "	.
REF00049	PDC_00021	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	52%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	7.45 h	.	48 h	25 &micro;M	MTT assay	"The results showed that all the conjugates had lower antiproliferative effects than Dox at the tested concentrations (Figure 2A); this may be related to inefficient release of Dox from the conjugate caused by the relative stable thioether bond linkage between Dox-SMP and GnRH analog. The antiproliferative effects of the three conjugates were close at 25, 50, and 75 uM. While at 100 uM, conjugate II exhibited higher inhibitory effect than that of I and III. "	.
REF00049	PDC_00021	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	45%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	7.45 h	.	48 h	50 &micro;M	MTT assay	"The results showed that all the conjugates had lower antiproliferative effects than Dox at the tested concentrations (Figure 2A); this may be related to inefficient release of Dox from the conjugate caused by the relative stable thioether bond linkage between Dox-SMP and GnRH analog. The antiproliferative effects of the three conjugates were close at 25, 50, and 75 uM. While at 100 uM, conjugate II exhibited higher inhibitory effect than that of I and III. "	.
REF00049	PDC_00021	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	28%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	7.45 h	.	48 h	75 &micro;M	MTT assay	"The results showed that all the conjugates had lower antiproliferative effects than Dox at the tested concentrations (Figure 2A); this may be related to inefficient release of Dox from the conjugate caused by the relative stable thioether bond linkage between Dox-SMP and GnRH analog. The antiproliferative effects of the three conjugates were close at 25, 50, and 75 uM. While at 100 uM, conjugate II exhibited higher inhibitory effect than that of I and III. "	"Although RNT with <sup>177</sup>Lu-DOTATATE/PSMA is known as a novel and effective therapy option for cancer that significantly improves the quality of life and survival of patients, it may have acute or chronic side effects. Therefore, any method that can ameliorate these side effects is useful in the RNT process. For this purpose, a few clinical studies have reported that antioxidants as free radical scavengers such as amifostine and vitamins C and E can reduce radioiodine-related side effects, particularly in salivary glands in thyroid cancer patients."
REF00049	PDC_00021	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	10%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	7.45 h	.	48 h	100 &micro;M	MTT assay	"The results showed that all the conjugates had lower antiproliferative effects than Dox at the tested concentrations (Figure 2A); this may be related to inefficient release of Dox from the conjugate caused by the relative stable thioether bond linkage between Dox-SMP and GnRH analog. The antiproliferative effects of the three conjugates were close at 25, 50, and 75 uM. While at 100 uM, conjugate II exhibited higher inhibitory effect than that of I and III. "	.
REF00049	PDC_00021	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	98%	%	.	.	.	.	Normal	NIH 3T3 cell	7.45 h	.	48 h	25 &micro;M	MTT assay	"However, by linking to [d-Cys6-des-Gly10-Pro9-NHEt]-GnRH, the cytotoxicity of Dox against 3T3 cells was reduced because the cell viability was over 87% after treatment with conjugate II in 25, 50, and 75 uM of equivalent concentration of Dox. Even at 100 uM, conjugate II maintained the cell viability to about 74% (Figure 2B). "	.
REF00049	PDC_00021	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	92%	%	.	.	.	.	Normal	NIH 3T3 cell	7.45 h	.	48 h	50 &micro;M	MTT assay	"However, by linking to [d-Cys6-des-Gly10-Pro9-NHEt]-GnRH, the cytotoxicity of Dox against 3T3 cells was reduced because the cell viability was over 87% after treatment with conjugate II in 25, 50, and 75 uM of equivalent concentration of Dox. Even at 100 uM, conjugate II maintained the cell viability to about 74% (Figure 2B). "	.
REF00049	PDC_00021	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	90%	%	.	.	.	.	Normal	NIH 3T3 cell	7.45 h	.	48 h	75 &micro;M	MTT assay	"However, by linking to [d-Cys6-des-Gly10-Pro9-NHEt]-GnRH, the cytotoxicity of Dox against 3T3 cells was reduced because the cell viability was over 87% after treatment with conjugate II in 25, 50, and 75 uM of equivalent concentration of Dox. Even at 100 uM, conjugate II maintained the cell viability to about 74% (Figure 2B). "	"In biological systems, antioxidants such as catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase are responsible for the elimination or reduction of the adverse effects of ROS, that is, they prevent or reduce ROS generation. Dietary antioxidants, such as vitamins E, A, and C, and anthocyanins and polyphenols have a role in the protection of cells against ROS damage."
REF00049	PDC_00021	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	75%	%	.	.	.	.	Normal	NIH 3T3 cell	7.45 h	.	48 h	100 &micro;M	MTT assay	"However, by linking to [d-Cys6-des-Gly10-Pro9-NHEt]-GnRH, the cytotoxicity of Dox against 3T3 cells was reduced because the cell viability was over 87% after treatment with conjugate II in 25, 50, and 75 uM of equivalent concentration of Dox. Even at 100 uM, conjugate II maintained the cell viability to about 74% (Figure 2B). "	.
REF00049	PDC_00021	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	108%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	7.45 h	.	48 h	25 &micro;M; with 10- &micro;M leuprolide for 2 hours	.	The combinations of conjugate II and leuprolide exhibited lower antiproliferative efficacy on MCF-7 cells than conjugate II individually at all the tested concentrations (Figure 3A).	.
REF00049	PDC_00021	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	72%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	7.45 h	.	48 h	50 &micro;M; with 10- &micro;M leuprolide for 2 hours	.	The combinations of conjugate II and leuprolide exhibited lower antiproliferative efficacy on MCF-7 cells than conjugate II individually at all the tested concentrations (Figure 3A).	.
REF00049	PDC_00021	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	50%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	7.45 h	.	48 h	75 &micro;M; with 10- &micro;M leuprolide for 2 hours	.	The combinations of conjugate II and leuprolide exhibited lower antiproliferative efficacy on MCF-7 cells than conjugate II individually at all the tested concentrations (Figure 3A).	"Vitamin C as a water-soluble vitamin is the reduced form of ascorbic acid. No significant adverse effect of taking high doses of vitamin C (over 2000 mg/day) has been reported due to the water-soluble feature of vitamin C. Vitamin C directly reacts with hydroxy, alkoxyl, and lipid peroxyl radicals and converts them to alcohol, water, and hydroperoxide lipid, respectively. It has been shown that taking vitamin C before radioiodine therapy can ameliorate the oxidative stress effect of radioiodine. The radioprotective effects of vitamin C are mainly due to its free radical scavenging activity."
REF00049	PDC_00021	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	48%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	7.45 h	.	48 h	100 &micro;M; with 10- &micro;M leuprolide for 2 hours	.	The combinations of conjugate II and leuprolide exhibited lower antiproliferative efficacy on MCF-7 cells than conjugate II individually at all the tested concentrations (Figure 3A).	.
REF00049	PDC_00019	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	0.59	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	5.23 h	.	48 h	25 &micro;M	MTT assay	"The results showed that all the conjugates had lower antiproliferative effects than Dox at the tested concentrations (Figure 2A); this may be related to inefficient release of Dox from the conjugate caused by the relative stable thioether bond linkage between Dox-SMP and GnRH analog. The antiproliferative effects of the three conjugates were close at 25, 50, and 75 uM. While at 100 uM, conjugate II exhibited higher inhibitory effect than that of I and III. "	.
REF00049	PDC_00019	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	0.5	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	5.23 h	.	48 h	50 &micro;M	MTT assay	"The results showed that all the conjugates had lower antiproliferative effects than Dox at the tested concentrations (Figure 2A); this may be related to inefficient release of Dox from the conjugate caused by the relative stable thioether bond linkage between Dox-SMP and GnRH analog. The antiproliferative effects of the three conjugates were close at 25, 50, and 75 uM. While at 100 uM, conjugate II exhibited higher inhibitory effect than that of I and III. "	.
REF00049	PDC_00019	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	0.38	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	5.23 h	.	48 h	75 &micro;M	MTT assay	"The results showed that all the conjugates had lower antiproliferative effects than Dox at the tested concentrations (Figure 2A); this may be related to inefficient release of Dox from the conjugate caused by the relative stable thioether bond linkage between Dox-SMP and GnRH analog. The antiproliferative effects of the three conjugates were close at 25, 50, and 75 uM. While at 100 uM, conjugate II exhibited higher inhibitory effect than that of I and III. "	"Vitamin C as a water-soluble vitamin is the reduced form of ascorbic acid. No significant adverse effect of taking high doses of vitamin C (over 2000 mg/day) has been reported due to the water-soluble feature of vitamin C. Vitamin C directly reacts with hydroxy, alkoxyl, and lipid peroxyl radicals and converts them to alcohol, water, and hydroperoxide lipid, respectively. It has been shown that taking vitamin C before radioiodine therapy can ameliorate the oxidative stress effect of radioiodine. The radioprotective effects of vitamin C are mainly due to its free radical scavenging activity."
REF00049	PDC_00019	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	0.3	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	5.23 h	.	48 h	100 &micro;M	MTT assay	"The results showed that all the conjugates had lower antiproliferative effects than Dox at the tested concentrations (Figure 2A); this may be related to inefficient release of Dox from the conjugate caused by the relative stable thioether bond linkage between Dox-SMP and GnRH analog. The antiproliferative effects of the three conjugates were close at 25, 50, and 75 uM. While at 100 uM, conjugate II exhibited higher inhibitory effect than that of I and III. "	.
REF00048	PDC_00029	Advanced prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	37.50%	%	.	.	.	Patients with advanced prostate cancer.	.	.	.	.	2 cycles	.	.	A maximum PSA decrease of 50% was achieved in 3 patients (37.5%). 	.
REF00048	PDC_00029	Advanced prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 toxicity	37.50%	%	.	.	.	Patients with advanced prostate cancer.	.	.	.	.	2 cycles	.	.	"No grade 4 toxicity was noticed, and grade 3 toxicity occurred in 3 patients (37.5%). "	.
REF00048	PDC_00029	Advanced prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	3.2 months	months	.	.	.	Patients with advanced prostate cancer.	.	.	.	.	2 cycles	.	.	"The median PSA-PFS and overall survival were 3.2 mo (95% confidence interval, 2.6-3.7 mo) and 14.0 mo (95% confidence interval, 6.2-21.8 mo), respectively."	.
REF00048	PDC_00029	Advanced prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	14 months	months	.	.	.	Patients with advanced prostate cancer.	.	.	.	.	2 cycles	.	.	"The median PSA-PFS and overall survival were 3.2 mo (95% confidence interval, 2.6-3.7 mo) and 14.0 mo (95% confidence interval, 6.2-21.8 mo), respectively."	.
REF00047	PDC_00208	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	13.89 &plusmn; 3.62 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00208	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.54 &plusmn; 0.67&micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00208	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.22 &plusmn; 0.13 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00205	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.93 &plusmn; 0.99 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	"In the case of MCF-7 cells, the uptake was at the lowest compound concentration (3.125 M) already 4 times higher for 10 (14.55%) than for K2 (3.5%). At 6.25 M concentration, 54.2% (10) and 19.35% (K2) of living cells were Dau positive, while at 12.5 M compound concentration, 94% (10) and 63.8% (K2) uptake could be detected. At the two highest concentrations (25 and 50 M), the cellular uptake on MCF-7 cells was between 96.45 and 100% for both conjugates. On HT-29 colon cancer cells, bioconjugate 10 (3.125 M) was taken up by 9.15% of the cells whereby the uptake of K2 was 3.25%. This tendency remains similar for the other concentrations, while at the highest concentration (50 M), a cellular uptake of 99.3% was detected for compound 10 and 92.5% for K2. Considering these results, we assume that the improved cytostatic effect is mainly related to the improved cellular uptake of compound 10"	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00205	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.36 &plusmn; 0.07 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"In the case of MCF-7 cells, the uptake was at the lowest compound concentration (3.125 M) already 4 times higher for 10 (14.55%) than for K2 (3.5%). At 6.25 M concentration, 54.2% (10) and 19.35% (K2) of living cells were Dau positive, while at 12.5 M compound concentration, 94% (10) and 63.8% (K2) uptake could be detected. At the two highest concentrations (25 and 50 M), the cellular uptake on MCF-7 cells was between 96.45 and 100% for both conjugates. On HT-29 colon cancer cells, bioconjugate 10 (3.125 M) was taken up by 9.15% of the cells whereby the uptake of K2 was 3.25%. This tendency remains similar for the other concentrations, while at the highest concentration (50 M), a cellular uptake of 99.3% was detected for compound 10 and 92.5% for K2. Considering these results, we assume that the improved cytostatic effect is mainly related to the improved cellular uptake of compound 10"	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00205	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.00 &plusmn; 1.33&micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"In the case of MCF-7 cells, the uptake was at the lowest compound concentration (3.125 M) already 4 times higher for 10 (14.55%) than for K2 (3.5%). At 6.25 M concentration, 54.2% (10) and 19.35% (K2) of living cells were Dau positive, while at 12.5 M compound concentration, 94% (10) and 63.8% (K2) uptake could be detected. At the two highest concentrations (25 and 50 M), the cellular uptake on MCF-7 cells was between 96.45 and 100% for both conjugates. On HT-29 colon cancer cells, bioconjugate 10 (3.125 M) was taken up by 9.15% of the cells whereby the uptake of K2 was 3.25%. This tendency remains similar for the other concentrations, while at the highest concentration (50 M), a cellular uptake of 99.3% was detected for compound 10 and 92.5% for K2. Considering these results, we assume that the improved cytostatic effect is mainly related to the improved cellular uptake of compound 10"	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00201	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.25 &plusmn; 2.51 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00201	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.60 &plusmn; 0.28 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00199	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.75 &plusmn; 0.86 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00199	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.89 &plusmn; 0.62 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00182	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.32 &plusmn; 1.32 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00182	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.75 &plusmn; 0.17 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00182	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.35 &plusmn; 1.93 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00198	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.34 &plusmn; 2.63 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00198	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.42 &plusmn; 0.39 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00181	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.70 &plusmn; 0.95 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00181	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.90 &plusmn; 0.58 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00181	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.88 &plusmn; 1.24 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00206	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.66 &plusmn; 1.76 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00206	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.81 &plusmn; 0.72 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00207	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	14.18 &plusmn; 3.59 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00207	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.88 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00207	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	14.33 &plusmn; 1.18 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00200	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.03 &plusmn; 2.51 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00200	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.64 &plusmn; 1.58 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00197	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	12.73 &plusmn; 3.10 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00197	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.56 &plusmn; 0.51 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00180	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.31 &plusmn; 0.90 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	"In the case of MCF-7 cells, the uptake was at the lowest compound concentration (3.125 M) already 4 times higher for 10 (14.55%) than for K2 (3.5%). At 6.25 M concentration, 54.2% (10) and 19.35% (K2) of living cells were Dau positive, while at 12.5 M compound concentration, 94% (10) and 63.8% (K2) uptake could be detected. At the two highest concentrations (25 and 50 M), the cellular uptake on MCF-7 cells was between 96.45 and 100% for both conjugates. On HT-29 colon cancer cells, bioconjugate 10 (3.125 M) was taken up by 9.15% of the cells whereby the uptake of K2 was 3.25%. This tendency remains similar for the other concentrations, while at the highest concentration (50 M), a cellular uptake of 99.3% was detected for compound 10 and 92.5% for K2. Considering these results, we assume that the improved cytostatic effect is mainly related to the improved cellular uptake of compound 10"	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00180	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.14 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"In the case of MCF-7 cells, the uptake was at the lowest compound concentration (3.125 M) already 4 times higher for 10 (14.55%) than for K2 (3.5%). At 6.25 M concentration, 54.2% (10) and 19.35% (K2) of living cells were Dau positive, while at 12.5 M compound concentration, 94% (10) and 63.8% (K2) uptake could be detected. At the two highest concentrations (25 and 50 M), the cellular uptake on MCF-7 cells was between 96.45 and 100% for both conjugates. On HT-29 colon cancer cells, bioconjugate 10 (3.125 M) was taken up by 9.15% of the cells whereby the uptake of K2 was 3.25%. This tendency remains similar for the other concentrations, while at the highest concentration (50 M), a cellular uptake of 99.3% was detected for compound 10 and 92.5% for K2. Considering these results, we assume that the improved cytostatic effect is mainly related to the improved cellular uptake of compound 10"	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00180	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.49 &plusmn; 0.53 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	"In the case of MCF-7 cells, the uptake was at the lowest compound concentration (3.125 M) already 4 times higher for 10 (14.55%) than for K2 (3.5%). At 6.25 M concentration, 54.2% (10) and 19.35% (K2) of living cells were Dau positive, while at 12.5 M compound concentration, 94% (10) and 63.8% (K2) uptake could be detected. At the two highest concentrations (25 and 50 M), the cellular uptake on MCF-7 cells was between 96.45 and 100% for both conjugates. On HT-29 colon cancer cells, bioconjugate 10 (3.125 M) was taken up by 9.15% of the cells whereby the uptake of K2 was 3.25%. This tendency remains similar for the other concentrations, while at the highest concentration (50 M), a cellular uptake of 99.3% was detected for compound 10 and 92.5% for K2. Considering these results, we assume that the improved cytostatic effect is mainly related to the improved cellular uptake of compound 10"	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00196	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	16.83 &plusmn; 0.66 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00196	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.57 &plusmn; 0.47 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00179	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	16.55 &plusmn; 0.30 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00179	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.81 &plusmn; 0.04 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00179	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.18 &plusmn; 0.18 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00202	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	18.00 &plusmn; 0.13 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00202	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.44 &plusmn; 0.51 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00203	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	17.84 &plusmn; 0.08 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00203	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.23 &plusmn; 0.40 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00047	PDC_00203	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	12.41 &plusmn; 2.30 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We obtained IC50 values in the low micromolar range on MCF-7 cells varying between 0.14 and 6.64 &mu;M. In the case of HT-29 colon cancer cells, the determined IC50 values were slightly higher and within a range of 3.31-19.10 &mu;M. With exception of compound 10, no significant difference of the cancer cell growth inhibitory effect of the novel bioconjugates and the control conjugates (K1 and K2) could be detected. However, the replacement of 3Trp by 3d-Tic in connection with the deletion of 2His led to an increased cytostatic effect of 10 on both of the analyzed cell lines. The IC50 value of bioconjugate 10 was more than 15-times lower on ER+ breast cancer MCF-7 cells and 5-times lower on colon cancer cells HT-29 compared to the control compound K2. Based on these promising findings, the growth inhibitory effects of conjugate 10 and the related 2His-3d-Tic (3, 5 and 12) conjugates, as well as the 10Gly-NH-Et (7 and 14) containing compounds, were studied on estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells. The corresponding IC50 values are shown in Table 2. The GnRH-III-Dau conjugate 10 revealed also on this cell line the highest anticancer activity with an IC50 value of 2.49 &mu;M. The comparison of the dose-dependent growth inhibitory effect of 10 and K2 on the three cancer cell lines is shown in Figure 1. Considering the results of all three cell lines, only compound 10 which contains the N-terminal modification 2His-d-Tic-Lys(Bu), displayed clearly a reduced cell viability, while the conjugates bearing other substitutions yielded IC50 values which vary only slightly in comparison to the controls. "	.
REF00046	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Mean absorbed dose	0.39 Gy/MBq	Gy/MBq	.	.	.	Patients with prostate cancer.	.	.	.	.	.	.	.	"Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (P < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%. "	.
REF00046	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Mean absorbed dose	0.44 Gy/MBq	Gy/MBq	.	.	.	Patients with prostate cancer.	.	.	.	.	.	.	.	"Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (P < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%. "	.
REF00046	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Mean absorbed dose	0.58 Gy/MBq	Gy/MBq	.	.	.	Patients with prostate cancer.	.	.	.	.	.	.	.	"Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (P < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%. "	.
REF00046	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Mean absorbed dose	0.1 Gy/MBq	Gy/MBq	.	.	.	Patients with prostate cancer.	.	.	.	.	.	.	.	"Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (P < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%. "	.
REF00046	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Mean absorbed dose	0.06 Gy/MBq	Gy/MBq	.	.	.	Patients with prostate cancer.	.	.	.	.	.	.	.	"Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (P < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%. "	.
REF00046	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Mean absorbed dose	0.11 Gy/MBq	Gy/MBq	.	.	.	Patients with prostate cancer.	.	.	.	.	.	.	.	"Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (P < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%. "	.
REF00046	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median whole-body tumor-absorbed dose	11.55 Gy/MBq	Gy/MBq	.	.	.	Patients with prostate cancer.	.	.	.	.	.	.	.	"Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (P < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%. "	.
REF00046	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median dose	14.1 Gy/MBq	Gy/MBq	.	.	.	Patients achieving a psa decline of less than 50%.	.	.	.	.	.	.	.	"Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (P < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%. "	.
REF00046	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median dose	9.6 Gy/MBq	Gy/MBq	.	.	.	Patients achieving a psa decline of at least 50%.	.	.	.	.	.	.	.	"Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (P < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%. "	.
REF00045	PDC_00027	Bronchial and gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Median progression-free survival (mPFS)	14.6 months	months	.	.	.	Patients with bronchial and gastroenteropancreatic neuroendocrine tumours.	.	.	.	.	Over two cycles	14.8 GBq	.	Median PFS was 14.6 months (95% CI 12.4-16.9) following R-PRRT and 14.2 months (95% CI 9.8-18.5) following RR-PRRT.	.
REF00045	PDC_00027	Bronchial and gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Median progression-free survival (mPFS)	14.2 months	months	.	.	.	Patients with bronchial and gastroenteropancreatic neuroendocrine tumours.	.	.	.	.	Over two cycles	14.8 GBq	.	Median PFS was 14.6 months (95% CI 12.4-16.9) following R-PRRT and 14.2 months (95% CI 9.8-18.5) following RR-PRRT.	.
REF00045	PDC_00027	Bronchial and gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Overall survival (OS)	80.8 months	months	.	.	.	Patients with bronchial and gastroenteropancreatic neuroendocrine tumours.	.	.	.	.	Over two cycles	14.8 GBq	.	Combined overall survival (OS) after I-PRRT plus R-PRRT and RR-PRRT was 80.8 months (95% CI 66.0-95.6). 	.
REF00045	PDC_00027	Bronchial and gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Grade 3/4 bone marrow toxicity	6.60%	%	.	.	.	Patients with bronchial and gastroenteropancreatic neuroendocrine tumours.	.	.	.	.	Over two cycles	14.8 GBq	.	"Grade III/IV bone marrow toxicity occurred in 6.6% and 7.7% of patients after R-PRRT and RR-PRRT, respectively. "	.
REF00045	PDC_00027	Bronchial and gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Grade 3/4 bone marrow toxicity	7.70%	%	.	.	.	Patients with bronchial and gastroenteropancreatic neuroendocrine tumours.	.	.	.	.	Over two cycles	14.8 GBq	.	"Grade III/IV bone marrow toxicity occurred in 6.6% and 7.7% of patients after R-PRRT and RR-PRRT, respectively. "	.
REF00045	PDC_00027	Bronchial and gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Disease occurrence rate	2.20%	%	.	.	.	Patients with bronchial and gastroenteropancreatic neuroendocrine tumours.	.	.	.	.	Over two cycles	14.8 GBq	.	The total incidence of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) was 2.2%. 	.
REF00044	PDC_00138	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	34.55 &micro;g mL<sup>-1</sup>	&micro;g mL<sup>-1</sup>	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	24.52&plusmn;13.17 h	.	.	.	MTT assay	The IC50 values for DOX-KGFRWR is 34.55 &mu;g mL-1.	.
REF00044	PDC_00138	Hepatocellular carcinoma	SMMC7721 pulmonary metastatic mouse model.	Obtained from the Model Organism Data	.	Half Maximal Inhibitory Concentration (IC50)	5.27 &micro;M	&micro;M	.	.	.	.	.	.	24.52&plusmn;13.17 h	.	.	.	.	"The IC50 values for KGFRWR, DOX, and DOX-KGFRWR against the MMP2 enzyme were 14.19, 8.68, and 5.27 10-6 m, respectively. "	.
REF00044	PDC_00138	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	.	Migration rates	19.90%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	24.52&plusmn;13.17 h	.	.	.	.	"Cells treated with DOX and DOX-KGFRWR exhibited markedly decreased migration, with migration rates of 39.4% and 19.9%, respectively, compared with those in the control, indicating that DOX-KGWRFR exerted a stronger inhibiting effect on migration than DOX."	.
REF00044	PDC_00138	Hepatocellular carcinoma	SMMC7721 tumorbearing mice.	Obtained from the Model Organism Data	.	Tumor volume	376 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	24.52&plusmn;13.17 h	.	.	.	.	"The antitumor efficacy of the DOX-KGFRWR nanofiber was superior to all other treatments, with a final tumor volume of 376 mm3. "	.
REF00044	PDC_00138	Hepatocellular carcinoma	SMMC7721 tumorbearing mice.	Obtained from the Model Organism Data	.	Tumor Growth Inhibition value (TGI)	78.51%	%	.	.	.	.	.	.	24.52&plusmn;13.17 h	.	.	.	.	"The antitumor efficacy of the DOX-KGFRWR nanofiber was superior to all other treatments, with a final tumor volume of 376 mm3. "	.
REF00044	PDC_00138	Hepatocellular carcinoma	SMMC7721 tumorbearing mice.	Obtained from the Model Organism Data	.	Percent survival	40 days	days	.	.	.	.	.	.	24.52&plusmn;13.17 h	.	30 days	.	.	DOX-KGFRWR has significantly prolonged survival rates. 	.
REF00044	PDC_00138	Hepatocellular carcinoma	SMMC7721 tumorbearing mice.	Obtained from the Model Organism Data	.	Percent survival	50%	%	.	.	.	.	.	.	24.52&plusmn;13.17 h	.	40 days	.	.	DOX-KGFRWR has significantly prolonged survival rates. 	.
REF00043	PDC_00057	Uveal melanoma	.	Revealed Based on the Cell Line Data	.	Cell viability	130%	%	.	.	.	.	Cutaneous melanoma	OCM-3 cell	2 h	.	72 h	40 nM	MTT assay	"OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3)."	.
REF00043	PDC_00057	Uveal melanoma	.	Revealed Based on the Cell Line Data	.	Cell viability	5%	%	.	.	.	.	Cutaneous melanoma	OCM-3 cell	2 h	.	72 h	1 &micro;M	MTT assay	"OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3)."	.
REF00043	PDC_00057	Uveal melanoma	.	Revealed Based on the Cell Line Data	.	Cell viability	6%	%	.	.	.	.	Cutaneous melanoma	OCM-3 cell	2 h	.	72 h	2.5 &micro;M	MTT assay	"OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3)."	.
REF00043	PDC_00057	Uveal melanoma	.	Revealed Based on the Cell Line Data	.	Cell viability	0%	%	.	.	.	.	Cutaneous melanoma	OCM-3 cell	2 h	.	72 h	5 &micro;M	MTT assay	"OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3)."	.
REF00043	PDC_00057	Uveal melanoma	.	Revealed Based on the Cell Line Data	.	Cell viability	120%	%	.	.	.	.	Cutaneous melanoma	OCM3<sub>DOX320</sub> cell	2 h	.	72 h	40 nM	MTT assay	"OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3)."	.
REF00043	PDC_00057	Uveal melanoma	.	Revealed Based on the Cell Line Data	.	Cell viability	105%	%	.	.	.	.	Cutaneous melanoma	OCM3<sub>DOX320</sub> cell	2 h	.	72 h	320 nM	MTT assay	"OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3)."	.
REF00043	PDC_00057	Uveal melanoma	.	Revealed Based on the Cell Line Data	.	Cell viability	80%	%	.	.	.	.	Cutaneous melanoma	OCM3<sub>DOX320</sub> cell	2 h	.	72 h	1 &micro;M	MTT assay	"OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3)."	.
REF00043	PDC_00057	Uveal melanoma	.	Revealed Based on the Cell Line Data	.	Cell viability	48%	%	.	.	.	.	Cutaneous melanoma	OCM3<sub>DOX320</sub> cell	2 h	.	72 h	2.5 &micro;M	MTT assay	"OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3)."	.
REF00043	PDC_00057	Uveal melanoma	.	Revealed Based on the Cell Line Data	.	Cell viability	25%	%	.	.	.	.	Cutaneous melanoma	OCM3<sub>DOX320</sub> cell	2 h	.	72 h	5 &micro;M	MTT assay	"OCM3DOX320cells did not show significant difference in cell viability in the presence of 1 uM DOX when compared to untreated control cells. 1 uM DOX induced significant cell death of OCM3 cells but did not cause significant cell death in OCM3DOX320cells, confirming DOX resistance. AN-152 at lower concentration (40 nM, 320 nM) increased cell proliferation significantly compared to equimolar dose of DOX which does not have any effect on cell viability at this concentration in OCM3 cells. However, higher concentrations of AN-152 can effectively inhibit cell proliferation in both cell lines. Higher concentrations (1-5 uM) of DOX and AN-152 showed no significantly different effect either on OCM3 or OCM3DOX320cells (Fig. 3)."	.
REF00042	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Radiation absorbed doses	0.29 &plusmn; 0.12 mGy/MBq	mGy/MBq	.	.	.	Patients with non-resectable histologically confirmed gastroenteropancreatic neuroendocrine tumors with normal kidney function.	.	.	.	.	14 days	600 mg m<sub>-2</sub> bovine serum albumin twice a day	.	"Radiation absorbed doses (mean &plusmn; standard deviation) were obtained as 0.29 &plusmn; 0.12 mGy/MBq for kidneys, 0.30 &plusmn; 0.18 mGy/MBq for liver, 0.63 &plusmn; 0.37 mGy/MBq for spleen, 0.019 &plusmn; 0.001 mGy/MBq for bone marrow and 3.85 &plusmn; 1.74 mGy/MBq for tumours in the case group and they were 0.31&plusmn; 0.26, 0.24 &plusmn; 0.14, 0.64 &plusmn; 0.42, 0.017 &plusmn; 0.016, 5.6 &plusmn; 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group."	.
REF00042	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Radiation absorbed doses	0.30 &plusmn; 0.18 mGy/MBq	mGy/MBq	.	.	.	Patients with non-resectable histologically confirmed gastroenteropancreatic neuroendocrine tumors with normal kidney function.	.	.	.	.	14 days	600 mg m<sub>-2</sub> bovine serum albumin twice a day	.	"Radiation absorbed doses (mean &plusmn; standard deviation) were obtained as 0.29 &plusmn; 0.12 mGy/MBq for kidneys, 0.30 &plusmn; 0.18 mGy/MBq for liver, 0.63 &plusmn; 0.37 mGy/MBq for spleen, 0.019 &plusmn; 0.001 mGy/MBq for bone marrow and 3.85 &plusmn; 1.74 mGy/MBq for tumours in the case group and they were 0.31&plusmn; 0.26, 0.24 &plusmn; 0.14, 0.64 &plusmn; 0.42, 0.017 &plusmn; 0.016, 5.6 &plusmn; 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group."	.
REF00042	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Radiation absorbed doses	0.63 &plusmn; 0.37 mGy/MBq	mGy/MBq	.	.	.	Patients with non-resectable histologically confirmed gastroenteropancreatic neuroendocrine tumors with normal kidney function.	.	.	.	.	14 days	600 mg m<sub>-2</sub> bovine serum albumin twice a day	.	"Radiation absorbed doses (mean &plusmn; standard deviation) were obtained as 0.29 &plusmn; 0.12 mGy/MBq for kidneys, 0.30 &plusmn; 0.18 mGy/MBq for liver, 0.63 &plusmn; 0.37 mGy/MBq for spleen, 0.019 &plusmn; 0.001 mGy/MBq for bone marrow and 3.85 &plusmn; 1.74 mGy/MBq for tumours in the case group and they were 0.31&plusmn; 0.26, 0.24 &plusmn; 0.14, 0.64 &plusmn; 0.42, 0.017 &plusmn; 0.016, 5.6 &plusmn; 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group."	.
REF00042	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Radiation absorbed doses	0.019 &plusmn; 0.001 mGy/MBq	mGy/MBq	.	.	.	Patients with non-resectable histologically confirmed gastroenteropancreatic neuroendocrine tumors with normal kidney function.	.	.	.	.	14 days	600 mg m<sub>-2</sub> bovine serum albumin twice a day	.	"Radiation absorbed doses (mean &plusmn; standard deviation) were obtained as 0.29 &plusmn; 0.12 mGy/MBq for kidneys, 0.30 &plusmn; 0.18 mGy/MBq for liver, 0.63 &plusmn; 0.37 mGy/MBq for spleen, 0.019 &plusmn; 0.001 mGy/MBq for bone marrow and 3.85 &plusmn; 1.74 mGy/MBq for tumours in the case group and they were 0.31&plusmn; 0.26, 0.24 &plusmn; 0.14, 0.64 &plusmn; 0.42, 0.017 &plusmn; 0.016, 5.6 &plusmn; 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group."	.
REF00042	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Radiation absorbed doses	3.85 &plusmn; 1.74 mGy/MBq	mGy/MBq	.	.	.	Patients with non-resectable histologically confirmed gastroenteropancreatic neuroendocrine tumors with normal kidney function.	.	.	.	.	14 days	600 mg m<sub>-2</sub> bovine serum albumin twice a day	.	"Radiation absorbed doses (mean &plusmn; standard deviation) were obtained as 0.29 &plusmn; 0.12 mGy/MBq for kidneys, 0.30 &plusmn; 0.18 mGy/MBq for liver, 0.63 &plusmn; 0.37 mGy/MBq for spleen, 0.019 &plusmn; 0.001 mGy/MBq for bone marrow and 3.85 &plusmn; 1.74 mGy/MBq for tumours in the case group and they were 0.31&plusmn; 0.26, 0.24 &plusmn; 0.14, 0.64 &plusmn; 0.42, 0.017 &plusmn; 0.016, 5.6 &plusmn; 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group."	.
REF00042	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Radiation absorbed doses	0.31 &plusmn; 0.26 mGy/MBq	mGy/MBq	.	.	.	Patients with non-resectable histologically confirmed gastroenteropancreatic neuroendocrine tumors with normal kidney function.	.	.	.	.	14 days	6.4 GBq-7.6 GBq	.	"Radiation absorbed doses (mean &plusmn; standard deviation) were obtained as 0.29 &plusmn; 0.12 mGy/MBq for kidneys, 0.30 &plusmn; 0.18 mGy/MBq for liver, 0.63 &plusmn; 0.37 mGy/MBq for spleen, 0.019 &plusmn; 0.001 mGy/MBq for bone marrow and 3.85 &plusmn; 1.74 mGy/MBq for tumours in the case group and they were 0.31&plusmn; 0.26, 0.24 &plusmn; 0.14, 0.64 &plusmn; 0.42, 0.017 &plusmn; 0.016, 5.6 &plusmn; 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group."	.
REF00042	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Radiation absorbed doses	0.24 &plusmn; 0.14 mGy/MBq	mGy/MBq	.	.	.	Patients with non-resectable histologically confirmed gastroenteropancreatic neuroendocrine tumors with normal kidney function.	.	.	.	.	14 days	6.4 GBq-7.6 GBq	.	"Radiation absorbed doses (mean &plusmn; standard deviation) were obtained as 0.29 &plusmn; 0.12 mGy/MBq for kidneys, 0.30 &plusmn; 0.18 mGy/MBq for liver, 0.63 &plusmn; 0.37 mGy/MBq for spleen, 0.019 &plusmn; 0.001 mGy/MBq for bone marrow and 3.85 &plusmn; 1.74 mGy/MBq for tumours in the case group and they were 0.31&plusmn; 0.26, 0.24 &plusmn; 0.14, 0.64 &plusmn; 0.42, 0.017 &plusmn; 0.016, 5.6 &plusmn; 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group."	.
REF00042	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Radiation absorbed doses	0.64 &plusmn; 0.42 mGy/MBq	mGy/MBq	.	.	.	Patients with non-resectable histologically confirmed gastroenteropancreatic neuroendocrine tumors with normal kidney function.	.	.	.	.	14 days	6.4 GBq-7.6 GBq	.	"Radiation absorbed doses (mean &plusmn; standard deviation) were obtained as 0.29 &plusmn; 0.12 mGy/MBq for kidneys, 0.30 &plusmn; 0.18 mGy/MBq for liver, 0.63 &plusmn; 0.37 mGy/MBq for spleen, 0.019 &plusmn; 0.001 mGy/MBq for bone marrow and 3.85 &plusmn; 1.74 mGy/MBq for tumours in the case group and they were 0.31&plusmn; 0.26, 0.24 &plusmn; 0.14, 0.64 &plusmn; 0.42, 0.017 &plusmn; 0.016, 5.6 &plusmn; 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group."	.
REF00042	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Radiation absorbed doses	0.017 &plusmn; 0.016 mGy/MBq	mGy/MBq	.	.	.	Patients with non-resectable histologically confirmed gastroenteropancreatic neuroendocrine tumors with normal kidney function.	.	.	.	.	14 days	6.4 GBq-7.6 GBq	.	"Radiation absorbed doses (mean &plusmn; standard deviation) were obtained as 0.29 &plusmn; 0.12 mGy/MBq for kidneys, 0.30 &plusmn; 0.18 mGy/MBq for liver, 0.63 &plusmn; 0.37 mGy/MBq for spleen, 0.019 &plusmn; 0.001 mGy/MBq for bone marrow and 3.85 &plusmn; 1.74 mGy/MBq for tumours in the case group and they were 0.31&plusmn; 0.26, 0.24 &plusmn; 0.14, 0.64 &plusmn; 0.42, 0.017 &plusmn; 0.016, 5.6 &plusmn; 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group."	.
REF00042	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Radiation absorbed doses	5.6 &plusmn; 11.27 mGy/MBq	mGy/MBq	.	.	.	Patients with non-resectable histologically confirmed gastroenteropancreatic neuroendocrine tumors with normal kidney function.	.	.	.	.	14 days	6.4 GBq-7.6 GBq	.	"Radiation absorbed doses (mean &plusmn; standard deviation) were obtained as 0.29 &plusmn; 0.12 mGy/MBq for kidneys, 0.30 &plusmn; 0.18 mGy/MBq for liver, 0.63 &plusmn; 0.37 mGy/MBq for spleen, 0.019 &plusmn; 0.001 mGy/MBq for bone marrow and 3.85 &plusmn; 1.74 mGy/MBq for tumours in the case group and they were 0.31&plusmn; 0.26, 0.24 &plusmn; 0.14, 0.64 &plusmn; 0.42, 0.017 &plusmn; 0.016, 5.6 &plusmn; 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group."	.
REF00041	PDC_00256	Metastatic Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.058 &plusmn; 0.015 &micro;M	&micro;M	.	.	.	.	Mammary carcinoma	4T1 cell	.	.	72 h	.	.	"P-(A5G27)-PTX was &tilde;4-fold more toxic than the nontargeted P-(A5G27scrm)-PTX copolymer, suggesting a faster (receptor-mediated) internalization (Figure 4)."	.
REF00041	PDC_00256	Metastatic Tumor	B16-F10 melanoma tumor-bearing mice model.	Obtained from the Model Organism Data	High Expreesion	Survival rate	40%	%	.	.	.	.	.	.	.	.	7 days	15 mg/kg PTX equivalent dose	.	"P-(A5G27)-PTX prolonged mice survival in 7 and 20% relative to the survival rates of free PTX and nontreated mice, respectively (Figure 5)."	.
REF00041	PDC_00256	Metastatic Tumor	4T1 tumor-bearing mice.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	48.50 days	days	.	.	.	.	.	.	.	.	.	15 mg/kg PTX equivalent dose	.	"The median survival of mice in the P-(A5G27)-PTX treatment group was longer than in P-(A5G27scrm)-PTX, P-(A5G27), and free PTX-treated groups (48.50 vs 40.5, 43, and 45.5, respectively); however, differences were nonsignificant (Figure 6B). "	.
REF00041	PDC_00257	Metastatic Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.221 &plusmn; 0.055 &micro;M	&micro;M	.	.	.	.	Mammary carcinoma	4T1 cell	.	.	72 h	.	.	"P-(A5G27)-PTX was &tilde;4-fold more toxic than the nontargeted P-(A5G27scrm)-PTX copolymer, suggesting a faster (receptor-mediated) internalization (Figure 4)."	.
REF00041	PDC_00257	Metastatic Tumor	4T1 tumor-bearing mice.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	40.5 days	days	.	.	.	.	.	.	.	.	.	15 mg/kg PTX equivalent dose	.	"The median survival of mice in the P-(A5G27)-PTX treatment group was longer than in P-(A5G27scrm)-PTX, P-(A5G27), and free PTX-treated groups (48.50 vs 40.5, 43, and 45.5, respectively); however, differences were nonsignificant (Figure 6B). "	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	28.10%	%	.	.	.	Patients with neuroendocrine tumours including high-grade (WHO G3) neuroendocrine tumours.	.	.	.	.	.	.	RECIST criteria assay	"Among 160 patients whose responses to treatment could be evaluated according to the RECIST criteria, 28.1% (n=45) had a progressive disease, 21.9% (n=35) had a stable disease, 46.9% (n=75) had a partial response and 3.1% (n=5) had a complete response."	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	21.90%	%	.	.	.	Patients with neuroendocrine tumours including high-grade (WHO G3) neuroendocrine tumours.	.	.	.	.	.	.	RECIST criteria assay	"Among 160 patients whose responses to treatment could be evaluated according to the RECIST criteria, 28.1% (n=45) had a progressive disease, 21.9% (n=35) had a stable disease, 46.9% (n=75) had a partial response and 3.1% (n=5) had a complete response."	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	46.90%	%	.	.	.	Patients with neuroendocrine tumours including high-grade (WHO G3) neuroendocrine tumours.	.	.	.	.	.	.	RECIST criteria assay	"Among 160 patients whose responses to treatment could be evaluated according to the RECIST criteria, 28.1% (n=45) had a progressive disease, 21.9% (n=35) had a stable disease, 46.9% (n=75) had a partial response and 3.1% (n=5) had a complete response."	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	3.10%	%	.	.	.	Patients with neuroendocrine tumours including high-grade (WHO G3) neuroendocrine tumours.	.	.	.	.	.	.	RECIST criteria assay	"Among 160 patients whose responses to treatment could be evaluated according to the RECIST criteria, 28.1% (n=45) had a progressive disease, 21.9% (n=35) had a stable disease, 46.9% (n=75) had a partial response and 3.1% (n=5) had a complete response."	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	36.4 months	months	.	.	.	Patients with neuroendocrine tumours including high-grade (WHO G3) neuroendocrine tumours.	.	.	.	.	.	.	Kaplan-Meier estimated assay	"The Kaplan-Meier estimated median PFS was 36.4 months, mean PFS was 38 months and the mean OS was 55 months. "	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Mean progression-free survival (mPFS)	38 months	months	.	.	.	Patients with neuroendocrine tumours including high-grade (WHO G3) neuroendocrine tumours.	.	.	.	.	.	.	Kaplan-Meier estimated assay	"The Kaplan-Meier estimated median PFS was 36.4 months, mean PFS was 38 months and the mean OS was 55 months. "	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Mean overall survival (mOS)	55 months	months	.	.	.	Patients with neuroendocrine tumours including high-grade (WHO G3) neuroendocrine tumours.	.	.	.	.	.	.	Kaplan-Meier estimated assay	"The Kaplan-Meier estimated median PFS was 36.4 months, mean PFS was 38 months and the mean OS was 55 months. "	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	74%	%	.	.	.	Patients with WHO grades I.	.	.	.	.	.	.	.	"The disease control rates in patients with WHO grades I, II and III were 74, 73 and 60%, respectively, and the OS rates were 61.9, 52.2 and 38.4 months, respectively. "	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	73%	%	.	.	.	Patients with WHO grades II.	.	.	.	.	.	.	.	"The disease control rates in patients with WHO grades I, II and III were 74, 73 and 60%, respectively, and the OS rates were 61.9, 52.2 and 38.4 months, respectively. "	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	60%	%	.	.	.	Patients with WHO grades III.	.	.	.	.	.	.	.	"The disease control rates in patients with WHO grades I, II and III were 74, 73 and 60%, respectively, and the OS rates were 61.9, 52.2 and 38.4 months, respectively. "	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	61.9 months	months	.	.	.	Patients with WHO grades I.	.	.	.	.	.	.	.	"The disease control rates in patients with WHO grades I, II and III were 74, 73 and 60%, respectively, and the OS rates were 61.9, 52.2 and 38.4 months, respectively. "	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	52.2 months	months	.	.	.	Patients with WHO grades II.	.	.	.	.	.	.	.	"The disease control rates in patients with WHO grades I, II and III were 74, 73 and 60%, respectively, and the OS rates were 61.9, 52.2 and 38.4 months, respectively. "	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	38.4 months	months	.	.	.	Patients with WHO grades III.	.	.	.	.	.	.	.	"The disease control rates in patients with WHO grades I, II and III were 74, 73 and 60%, respectively, and the OS rates were 61.9, 52.2 and 38.4 months, respectively. "	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 toxicity	33.90%	%	.	.	.	Patients with neuroendocrine tumours including high-grade (WHO G3) neuroendocrine tumours.	.	.	.	.	.	.	.	"We observed no major renal toxicity except a minor increase (11.1%) in average serum creatinine levels. In 33.9% (n=56) of the patients, grade I toxicity; in 9.1% (n=15), grade II; and in 1.2% (n=2), grade III toxicity were observed."	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 toxicity	9.10%	%	.	.	.	Patients with neuroendocrine tumours including high-grade (WHO G3) neuroendocrine tumours.	.	.	.	.	.	.	.	"We observed no major renal toxicity except a minor increase (11.1%) in average serum creatinine levels. In 33.9% (n=56) of the patients, grade I toxicity; in 9.1% (n=15), grade II; and in 1.2% (n=2), grade III toxicity were observed."	.
REF00040	PDC_00027	High-grade (WHO G3) neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 toxicity	1.20%	%	.	.	.	Patients with neuroendocrine tumours including high-grade (WHO G3) neuroendocrine tumours.	.	.	.	.	.	.	.	"We observed no major renal toxicity except a minor increase (11.1%) in average serum creatinine levels. In 33.9% (n=56) of the patients, grade I toxicity; in 9.1% (n=15), grade II; and in 1.2% (n=2), grade III toxicity were observed."	.
REF00038	PDC_00309	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	98%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	2.5 &micro;M	MTS assay	pHLIP-M-DOX had a negligible effect on HeLa cell proliferation when incubated on cells at either pH at pHLIP concentrations as high as 10 &mu;M. This is consistent with our imaging data that showed no release of DOX into the cell interior at either pH. 	.
REF00038	PDC_00309	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	97%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	5 &micro;M	MTS assay	pHLIP-M-DOX had a negligible effect on HeLa cell proliferation when incubated on cells at either pH at pHLIP concentrations as high as 10 &mu;M. This is consistent with our imaging data that showed no release of DOX into the cell interior at either pH. 	.
REF00038	PDC_00309	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	100%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	2.5 &micro;M	MTS assay	pHLIP-M-DOX had a negligible effect on HeLa cell proliferation when incubated on cells at either pH at pHLIP concentrations as high as 10 &mu;M. This is consistent with our imaging data that showed no release of DOX into the cell interior at either pH. 	.
REF00038	PDC_00309	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	99%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	5 &micro;M	MTS assay	pHLIP-M-DOX had a negligible effect on HeLa cell proliferation when incubated on cells at either pH at pHLIP concentrations as high as 10 &mu;M. This is consistent with our imaging data that showed no release of DOX into the cell interior at either pH. 	.
REF00038	PDC_00309	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	97%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	10 &micro;M	MTS assay	pHLIP-M-DOX had a negligible effect on HeLa cell proliferation when incubated on cells at either pH at pHLIP concentrations as high as 10 &mu;M. This is consistent with our imaging data that showed no release of DOX into the cell interior at either pH. 	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	50%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	0.16 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 10 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	45%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	0.31 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 11 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	42%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	0.63 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 12 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	20%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	1.3 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 13 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	22%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	2.5 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 14 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	22%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	5.0 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 15 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	18%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	10 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 16 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	95%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	0.16 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 17 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	98%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	0.31 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 18 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	90%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	0.63 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 19 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	100%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	1.3 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 20 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	100%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	2.5 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 21 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	100%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	5.0 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 22 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	99%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	10 &micro;M	MTS assay	"HeLa cells treated with pHLIP-S-S-DOX at low pH showed significant toxicity (&tilde;50% viability at the lowest concentration tested (0.16 &mu;M pHLIP)) which, in this construct, corresponds to the DOX concentration. Cellular viability tracked inversely with increasing pHLIP conjugate concentration, peaking at &tilde;18% viability at 23 &mu;M. "	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	38%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	0.16 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	30%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	0.31 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	30%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	0.63 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00038	PDC_00312	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	30%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	1.3 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00038	PDC_00310	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	20%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	2.5 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00038	PDC_00310	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	20%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	5.0 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00038	PDC_00310	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	15%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	10 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00038	PDC_00310	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	90%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	0.16 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00038	PDC_00310	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	90%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	0.31 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00038	PDC_00310	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	95%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	0.63 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00038	PDC_00310	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	90%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	1.3 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00038	PDC_00310	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	100%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	2.5 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00038	PDC_00310	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	100%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	5.0 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00038	PDC_00310	Tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	98%	%	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	10 &micro;M	MTS assay	"The cytotoxicity data for the pHLIP-PAMAM-DOX conjugate mirrored quite closely that of the pHLIP-S-S-DOX conjugate, particularly at the higher concentrations (>1.25 &mu;M). However, at lower pHLIP concentrations (0.16 &mu;M-0.63 &mu;M), the PAMAM conjugate exhibited higher cytotoxicity than the single DOX conjugate (&tilde;up to 17% higher toxicity)."	.
REF00034	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	6%	%	.	.	.	Patients with advanced GEP-neuroendocrine tumour.	.	.	.	.	Four or five cycles	18.5 GBq/27.8 GBq 	.	"Two patients (6%) achieved a partial response and 21 (64%) showed stable disease, giving a disease control rate (DCR) of 70%."	.
REF00034	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	64%	%	.	.	.	Patients with advanced GEP-neuroendocrine tumour.	.	.	.	.	Four or five cycles	18.5 GBq/27.8 GBq 	.	"Two patients (6%) achieved a partial response and 21 (64%) showed stable disease, giving a disease control rate (DCR) of 70%."	.
REF00034	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	70%	%	.	.	.	Patients with advanced GEP-neuroendocrine tumour.	.	.	.	.	Four or five cycles	18.5 GBq/27.8 GBq 	.	"Two patients (6%) achieved a partial response and 21 (64%) showed stable disease, giving a disease control rate (DCR) of 70%."	.
REF00034	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	23 months	months	.	.	.	Patients with advanced GEP-neuroendocrine tumour.	.	.	.	.	Four or five cycles	18.5 GBq/27.8 GBq 	.	The median progression-free survival (PFS) was 23 months (95% CI 14.9-31.0 months) and the median overall survival was 52.9 months (95% CI 17.1-68.9 months). 	.
REF00034	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	52.9 months	months	.	.	.	Patients with advanced GEP-neuroendocrine tumour.	.	.	.	.	Four or five cycles	18.5 GBq/27.8 GBq 	.	The median progression-free survival (PFS) was 23 months (95% CI 14.9-31.0 months) and the median overall survival was 52.9 months (95% CI 17.1-68.9 months). 	.
REF00037	PDC_00153	Bladder cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.24 &micro;M	&micro;M	.	.	.	.	Bladder cancer	Bladder cancer cell	.	.	24 h	.	MTT assay	The 50% inhibitory concentration (IC50) of GA-TAT at 24 h was 1.24 uM	"These findings suggest that GA-TAT-induced EJ cell apoptosis is mediated via ROS production. Our study demonstrated that GA-TAT enhanced the pro-apoptotic effect via increasing caspase-3 and caspase-9 processing and activities and decreasing the Bcl-2/Bax ratio, which were regulated by intracellular ROS."
REF00037	PDC_00153	Bladder cancer	.	Revealed Based on the Cell Line Data	.	Inhibition rate	46.4% &plusmn; 4.86%	%	.	.	.	.	Bladder carcinoma	EJ-1 cell	.	.	24 h	1.0 &micro;M	.	"However, after treatment with GA-TAT, the percentage of apoptotic cells was greatly increased to 46.4%&plusmn;4.86%."	"These findings suggest that GA-TAT-induced EJ cell apoptosis is mediated via ROS production. Our study demonstrated that GA-TAT enhanced the pro-apoptotic effect via increasing caspase-3 and caspase-9 processing and activities and decreasing the Bcl-2/Bax ratio, which were regulated by intracellular ROS."
REF00036	PDC_00261	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	80.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	24 h	50 &micro;M	XTT assay	All three P4-PDC-coated gold nanoparticles pre-incubated for 24 or 48 h induced statistically similar cytotoxicity in A20 to that induced by freshly prepared PDC4 and to coated particles without pre-incubation (the latter data not shown). 	.
REF00036	PDC_00261	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	72.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	48 h	50 &micro;M	XTT assay	All three P4-PDC-coated gold nanoparticles pre-incubated for 24 or 48 h induced statistically similar cytotoxicity in A20 to that induced by freshly prepared PDC4 and to coated particles without pre-incubation (the latter data not shown). 	"In biological systems, antioxidants such as catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase are responsible for the elimination or reduction of the adverse effects of ROS, that is, they prevent or reduce ROS generation. Dietary antioxidants, such as vitamins E, A, and C, and anthocyanins and polyphenols have a role in the protection of cells against ROS damage."
REF00036	PDC_00261	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	40.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	72 h	50 &micro;M	XTT assay	All three P4-PDC-coated gold nanoparticles pre-incubated for 24 or 48 h induced statistically similar cytotoxicity in A20 to that induced by freshly prepared PDC4 and to coated particles without pre-incubation (the latter data not shown). 	.
REF00036	PDC_00263	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	80.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	24 h	50 &micro;M	XTT assay	All three P4-PDC-coated gold nanoparticles pre-incubated for 24 or 48 h induced statistically similar cytotoxicity in A20 to that induced by freshly prepared PDC4 and to coated particles without pre-incubation (the latter data not shown). 	.
REF00036	PDC_00263	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	78.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	48 h	50 &micro;M	XTT assay	All three P4-PDC-coated gold nanoparticles pre-incubated for 24 or 48 h induced statistically similar cytotoxicity in A20 to that induced by freshly prepared PDC4 and to coated particles without pre-incubation (the latter data not shown). 	"Vitamin C as a water-soluble vitamin is the reduced form of ascorbic acid. No significant adverse effect of taking high doses of vitamin C (over 2000 mg/day) has been reported due to the water-soluble feature of vitamin C. Vitamin C directly reacts with hydroxy, alkoxyl, and lipid peroxyl radicals and converts them to alcohol, water, and hydroperoxide lipid, respectively. It has been shown that taking vitamin C before radioiodine therapy can ameliorate the oxidative stress effect of radioiodine. The radioprotective effects of vitamin C are mainly due to its free radical scavenging activity."
REF00036	PDC_00263	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	45.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	72 h	50 &micro;M	XTT assay	All three P4-PDC-coated gold nanoparticles pre-incubated for 24 or 48 h induced statistically similar cytotoxicity in A20 to that induced by freshly prepared PDC4 and to coated particles without pre-incubation (the latter data not shown). 	.
REF00036	PDC_00259	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	80.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	24 h	50 &micro;M	XTT assay	All three P4-PDC-coated gold nanoparticles pre-incubated for 24 or 48 h induced statistically similar cytotoxicity in A20 to that induced by freshly prepared PDC4 and to coated particles without pre-incubation (the latter data not shown). 	.
REF00036	PDC_00259	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	75.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	48 h	50 &micro;M	XTT assay	All three P4-PDC-coated gold nanoparticles pre-incubated for 24 or 48 h induced statistically similar cytotoxicity in A20 to that induced by freshly prepared PDC4 and to coated particles without pre-incubation (the latter data not shown). 	.
REF00036	PDC_00259	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	30.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	72 h	50 &micro;M	XTT assay	All three P4-PDC-coated gold nanoparticles pre-incubated for 24 or 48 h induced statistically similar cytotoxicity in A20 to that induced by freshly prepared PDC4 and to coated particles without pre-incubation (the latter data not shown). 	.
REF00036	PDC_00260	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	70.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	72 h	50 &micro;M	XTT assay	"Conjugation of the drugs to P4 affected their efficacy toward A20 cells. For chlorambucil and melphalan, conjugation reduced the cytotoxic effect and this was significant for chlorambucil at 25 &mu;M (p = 0.0013). On the other hand, conjugation significantly improved the cytotoxic effect of bendamustine at 25 (p = 0.043) and 50 &mu;M (p = 0.048). The efficacies of all P6-conjugates were significantly lower than those of P4-conjugates at concentrations above 10 &mu;M."	.
REF00036	PDC_00262	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	75.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	72 h	50 &micro;M	XTT assay	"Conjugation of the drugs to P4 affected their efficacy toward A20 cells. For chlorambucil and melphalan, conjugation reduced the cytotoxic effect and this was significant for chlorambucil at 25 &mu;M (p = 0.0013). On the other hand, conjugation significantly improved the cytotoxic effect of bendamustine at 25 (p = 0.043) and 50 &mu;M (p = 0.048). The efficacies of all P6-conjugates were significantly lower than those of P4-conjugates at concentrations above 10 &mu;M."	.
REF00036	PDC_00258	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	70.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	72 h	50 &micro;M	XTT assay	"Conjugation of the drugs to P4 affected their efficacy toward A20 cells. For chlorambucil and melphalan, conjugation reduced the cytotoxic effect and this was significant for chlorambucil at 25 &mu;M (p = 0.0013). On the other hand, conjugation significantly improved the cytotoxic effect of bendamustine at 25 (p = 0.043) and 50 &mu;M (p = 0.048). The efficacies of all P6-conjugates were significantly lower than those of P4-conjugates at concentrations above 10 &mu;M."	.
REF00036	PDC_00265	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	22.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	72 h	50 &micro;M	XTT assay	"Conjugation of the drugs to P4 affected their efficacy toward A20 cells. For chlorambucil and melphalan, conjugation reduced the cytotoxic effect and this was significant for chlorambucil at 25 &mu;M (p = 0.0013). On the other hand, conjugation significantly improved the cytotoxic effect of bendamustine at 25 (p = 0.043) and 50 &mu;M (p = 0.048). The efficacies of all P6-conjugates were significantly lower than those of P4-conjugates at concentrations above 10 &mu;M."	.
REF00036	PDC_00266	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	25.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	72 h	50 &micro;M	XTT assay	"Conjugation of the drugs to P4 affected their efficacy toward A20 cells. For chlorambucil and melphalan, conjugation reduced the cytotoxic effect and this was significant for chlorambucil at 25 &mu;M (p = 0.0013). On the other hand, conjugation significantly improved the cytotoxic effect of bendamustine at 25 (p = 0.043) and 50 &mu;M (p = 0.048). The efficacies of all P6-conjugates were significantly lower than those of P4-conjugates at concentrations above 10 &mu;M."	.
REF00036	PDC_00264	Tumor	.	Revealed Based on the Cell Line Data	.	A20 growth inhibition	28.00%	%	.	.	.	.	Mouse reticulum cell sarcoma	A20 cell	.	.	72 h	50 &micro;M	XTT assay	"Conjugation of the drugs to P4 affected their efficacy toward A20 cells. For chlorambucil and melphalan, conjugation reduced the cytotoxic effect and this was significant for chlorambucil at 25 &mu;M (p = 0.0013). On the other hand, conjugation significantly improved the cytotoxic effect of bendamustine at 25 (p = 0.043) and 50 &mu;M (p = 0.048). The efficacies of all P6-conjugates were significantly lower than those of P4-conjugates at concentrations above 10 &mu;M."	.
REF00035	PDC_00002	Breast cancer	BALB/c mice syngeneic breast-cancer metastasis model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Number of Lung metastases nodules	5	.	.	.	.	.	.	.	.	.	2 weeks	24.5 mg/kg	.	"We observed the clear and significant (p < 0.0001) beneficial effects of the dimer drug on lung metastasis (Figure5A,B), with a reduction of the gross lung-metastasis count by more than 75% compared with those in the control and Abraxane groups."	.
REF00032	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	56.00%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Total of 213 cycles; 3 cycles with every 8 weeks	6.016 &plusmn; 0.543 GBq	.	A PSA decline &ge;50% and some PSA decline occurred in 56% and 66% of the patients.	.
REF00032	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	66%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Total of 213 cycles; 3 cycles with every 8 weeks	6.016 &plusmn; 0.543 GBq	.	A PSA decline &ge;50% and some PSA decline occurred in 56% and 66% of the patients.	.
REF00031	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Mortality rate	49%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	351 cycles	.	.	"A total of 51 patients (49%) died during the observation period. The majority of patients (97%) presented with bone metastases, 77% with lymph node metastases and 32% with visceral metastases."	.
REF00031	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Bone metastases	97%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	351 cycles	.	.	"A total of 51 patients (49%) died during the observation period. The majority of patients (97%) presented with bone metastases, 77% with lymph node metastases and 32% with visceral metastases."	.
REF00031	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Lymph node metastases	77%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	351 cycles	.	.	"A total of 51 patients (49%) died during the observation period. The majority of patients (97%) presented with bone metastases, 77% with lymph node metastases and 32% with visceral metastases."	.
REF00031	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Visceral metastases	32%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	351 cycles	.	.	"A total of 51 patients (49%) died during the observation period. The majority of patients (97%) presented with bone metastases, 77% with lymph node metastases and 32% with visceral metastases."	.
REF00031	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	67%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	351 cycles	.	.	Any PSA decline occurred in 70 (67%) and a PSA decline &ge;50% in 34 (33%) of patients after the first cycle.	.
REF00031	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	33.00%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	351 cycles	.	.	Any PSA decline occurred in 70 (67%) and a PSA decline &ge;50% in 34 (33%) of patients after the first cycle.	.
REF00031	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	56.0 weeks	weeks	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	351 cycles	.	.	The median OS was 56.0 weeks (95%CI: 50.5-61.5).	.
REF00030	PDC_00053	Tumor	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	9.27 &plusmn; 3.56 &micro;M	&micro;M	.	.	.	.	Lung adenocarcinoma	A-549 cell	23.67 &plusmn; 0.35 h	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	.	.	CCK-8 assay	"Whereas conjugation of a peptide would hinder the passive diffusion route, resulting in higher IC50 values for the peptide-DOX-conjugates (9.27 &plusmn; 3.56 uM for ABD-RGDK-DOXO and 11.21 &plusmn; 4.54 uM for ABD-RPARPAR-DOXO, respectively)."	.
REF00030	PDC_00053	Tumor	Tumor-bearing BALB/c nude mice.	Obtained from the Model Organism Data	.	Retarded the tumor growth rate	47.78%	%	.	.	.	.	.	.	23.67 &plusmn; 0.35 h	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	20 days	3.0 mg/kg doxorubicin equivalent	.	"The doxorubicin, DOXO-EMCH, ABD-RGDK-DOXO, and ABD-RPARPAR-DOXO retarded the tumor growth rate by 24.28, 25.67, 47.78, and 47.09% on day 20, respectively."	.
REF00030	PDC_00054	Tumor	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	11.21 &plusmn; 4.54 &micro;M	&micro;M	.	.	.	.	Lung adenocarcinoma	A-549 cell	23.88 &plusmn; 0.94 h	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	.	.	CCK-8 assay	"Whereas conjugation of a peptide would hinder the passive diffusion route, resulting in higher IC50 values for the peptide-DOX-conjugates (9.27 &plusmn; 3.56 uM for ABD-RGDK-DOXO and 11.21 &plusmn; 4.54 uM for ABD-RPARPAR-DOXO, respectively)."	.
REF00030	PDC_00054	Tumor	Tumor-bearing BALB/c nude mice.	Obtained from the Model Organism Data	.	Retarded the tumor growth rate	47.09%	%	.	.	.	.	.	.	23.88 &plusmn; 0.94 h	"This would indicate a cellular uptake mediated by the CPP part of the conjugate and only a minor influence of integrin receptor-mediated endocytosis.All in all, we concluded that after interfering with the v3 receptor, the dual functional conjugate prefers CPP-mediated cellular internalization."	20 days	3.0 mg/kg doxorubicin equivalent	.	"The doxorubicin, DOXO-EMCH, ABD-RGDK-DOXO, and ABD-RPARPAR-DOXO retarded the tumor growth rate by 24.28, 25.67, 47.78, and 47.09% on day 20, respectively."	.
REF00029	PDC_00097	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	102.33 &plusmn; 38.92 nM	nM	.	.	.	.	Melanoma	B16 cell	.	.	48 h	.	.	The IC50 of QCCD@NPs and QSSD@NPs (389.05&plusmn;75.25 nM and 245.47&plusmn;37.54 nM) on B16 cells seemed much higher than the values of RCCD@NPs and RSSD@NPs (102.33&plusmn;38.92 nM and 21.38&plusmn;4.32 nM). The cytotoxicity of APDC@NPs on HUVEC showed a similar pattern.	.
REF00029	PDC_00097	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	407.38 &plusmn; 54.05 nM	nM	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	.	The IC50 of QCCD@NPs and QSSD@NPs (389.05&plusmn;75.25 nM and 245.47&plusmn;37.54 nM) on B16 cells seemed much higher than the values of RCCD@NPs and RSSD@NPs (102.33&plusmn;38.92 nM and 21.38&plusmn;4.32 nM). The cytotoxicity of APDC@NPs on HUVEC showed a similar pattern.	.
REF00029	PDC_00097	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	33.84 &plusmn; 6.30 nM	nM	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	.	48 h	.	.	The IC50 of QCCD@NPs and QSSD@NPs (389.05&plusmn;75.25 nM and 245.47&plusmn;37.54 nM) on B16 cells seemed much higher than the values of RCCD@NPs and RSSD@NPs (102.33&plusmn;38.92 nM and 21.38&plusmn;4.32 nM). The cytotoxicity of APDC@NPs on HUVEC showed a similar pattern.	.
REF00029	PDC_00097	Tumor	Tumor-bearing C57BL/6 mice model.	Obtained from the Model Organism Data	High Expreesion	Tumer volume	2100 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	Given every other day for a total of five times	400 &micro;g/kg (calculated by free DM1)	.	"It was demonstrated here, RCCD@NPs and RSSD@NPs exhibited significantly better tumor-growth inhibition compared with that of the free DM1, QCCD@NPs or QSSD@NPs (Figure (Figure4A).4A). RSSD@NPs showed the most suppression on B16 tumor up to 25 days, and resulted in a tumor volume 4 times smaller than the saline group at the end of the experiment. The final tumor volumes in various nano-DDS groups ranked from the greatest to the least: QCCD@NPs, QSSD@NPs>DM1>RCCD@NPs>RSSD@NPs. Almost the same trends were found in terms of tumor weight and tumor size (Figures (Figures4B,4B, C). "	.
REF00029	PDC_00099	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	21.38 &plusmn; 4.32 nM	nM	.	.	.	.	Melanoma	B16 cell	.	.	48 h	.	.	The IC50 of QCCD@NPs and QSSD@NPs (389.05&plusmn;75.25 nM and 245.47&plusmn;37.54 nM) on B16 cells seemed much higher than the values of RCCD@NPs and RSSD@NPs (102.33&plusmn;38.92 nM and 21.38&plusmn;4.32 nM). The cytotoxicity of APDC@NPs on HUVEC showed a similar pattern.	.
REF00029	PDC_00099	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	302.00 &plusmn; 72.91 nM	nM	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	.	The IC50 of QCCD@NPs and QSSD@NPs (389.05&plusmn;75.25 nM and 245.47&plusmn;37.54 nM) on B16 cells seemed much higher than the values of RCCD@NPs and RSSD@NPs (102.33&plusmn;38.92 nM and 21.38&plusmn;4.32 nM). The cytotoxicity of APDC@NPs on HUVEC showed a similar pattern.	.
REF00029	PDC_00099	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	20.42 &plusmn; 4.70 nM	nM	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	.	48 h	.	.	The IC50 of QCCD@NPs and QSSD@NPs (389.05&plusmn;75.25 nM and 245.47&plusmn;37.54 nM) on B16 cells seemed much higher than the values of RCCD@NPs and RSSD@NPs (102.33&plusmn;38.92 nM and 21.38&plusmn;4.32 nM). The cytotoxicity of APDC@NPs on HUVEC showed a similar pattern.	.
REF00029	PDC_00099	Tumor	.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumer volume	1800 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	Given every other day for a total of five times	400 &micro;g/kg (calculated by free DM1)	.	"It was demonstrated here, RCCD@NPs and RSSD@NPs exhibited significantly better tumor-growth inhibition compared with that of the free DM1, QCCD@NPs or QSSD@NPs (Figure (Figure4A).4A). RSSD@NPs showed the most suppression on B16 tumor up to 25 days, and resulted in a tumor volume 4 times smaller than the saline group at the end of the experiment. The final tumor volumes in various nano-DDS groups ranked from the greatest to the least: QCCD@NPs, QSSD@NPs>DM1>RCCD@NPs>RSSD@NPs. Almost the same trends were found in terms of tumor weight and tumor size (Figures (Figures4B,4B, C). "	.
REF00029	PDC_00100	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	389.05 &plusmn; 75.25 nM	nM	.	.	.	.	Melanoma	B16 cell	.	.	48 h	.	.	The IC50 of QCCD@NPs and QSSD@NPs (389.05&plusmn;75.25 nM and 245.47&plusmn;37.54 nM) on B16 cells seemed much higher than the values of RCCD@NPs and RSSD@NPs (102.33&plusmn;38.92 nM and 21.38&plusmn;4.32 nM). The cytotoxicity of APDC@NPs on HUVEC showed a similar pattern.	.
REF00029	PDC_00100	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	331.13 &plusmn; 85.56 nM	nM	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	.	The IC50 of QCCD@NPs and QSSD@NPs (389.05&plusmn;75.25 nM and 245.47&plusmn;37.54 nM) on B16 cells seemed much higher than the values of RCCD@NPs and RSSD@NPs (102.33&plusmn;38.92 nM and 21.38&plusmn;4.32 nM). The cytotoxicity of APDC@NPs on HUVEC showed a similar pattern.	.
REF00029	PDC_00100	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	67.61 &plusmn; 13.67 nM	nM	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	.	48 h	.	.	The IC50 of QCCD@NPs and QSSD@NPs (389.05&plusmn;75.25 nM and 245.47&plusmn;37.54 nM) on B16 cells seemed much higher than the values of RCCD@NPs and RSSD@NPs (102.33&plusmn;38.92 nM and 21.38&plusmn;4.32 nM). The cytotoxicity of APDC@NPs on HUVEC showed a similar pattern.	.
REF00029	PDC_00100	Tumor	.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumer volume	2400 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	Given every other day for a total of five times	400 &micro;g/kg (calculated by free DM1)	.	"It was demonstrated here, RCCD@NPs and RSSD@NPs exhibited significantly better tumor-growth inhibition compared with that of the free DM1, QCCD@NPs or QSSD@NPs (Figure (Figure4A).4A). RSSD@NPs showed the most suppression on B16 tumor up to 25 days, and resulted in a tumor volume 4 times smaller than the saline group at the end of the experiment. The final tumor volumes in various nano-DDS groups ranked from the greatest to the least: QCCD@NPs, QSSD@NPs>DM1>RCCD@NPs>RSSD@NPs. Almost the same trends were found in terms of tumor weight and tumor size (Figures (Figures4B,4B, C). "	.
REF00029	PDC_00101	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	245.47 &plusmn; 37.54 nM	nM	.	.	.	.	Melanoma	B16 cell	.	.	48 h	.	.	The IC50 of QCCD@NPs and QSSD@NPs (389.05&plusmn;75.25 nM and 245.47&plusmn;37.54 nM) on B16 cells seemed much higher than the values of RCCD@NPs and RSSD@NPs (102.33&plusmn;38.92 nM and 21.38&plusmn;4.32 nM). The cytotoxicity of APDC@NPs on HUVEC showed a similar pattern.	.
REF00029	PDC_00101	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	371.53 &plusmn; 94.49 nM	nM	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	.	The IC50 of QCCD@NPs and QSSD@NPs (389.05&plusmn;75.25 nM and 245.47&plusmn;37.54 nM) on B16 cells seemed much higher than the values of RCCD@NPs and RSSD@NPs (102.33&plusmn;38.92 nM and 21.38&plusmn;4.32 nM). The cytotoxicity of APDC@NPs on HUVEC showed a similar pattern.	.
REF00029	PDC_00101	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	154.88 &plusmn; 31.85 nM	nM	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	.	48 h	.	.	The IC50 of QCCD@NPs and QSSD@NPs (389.05&plusmn;75.25 nM and 245.47&plusmn;37.54 nM) on B16 cells seemed much higher than the values of RCCD@NPs and RSSD@NPs (102.33&plusmn;38.92 nM and 21.38&plusmn;4.32 nM). The cytotoxicity of APDC@NPs on HUVEC showed a similar pattern.	.
REF00029	PDC_00101	Tumor	.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumer volume	5200 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	Given every other day for a total of five times	400 &micro;g/kg (calculated by free DM1)	.	"It was demonstrated here, RCCD@NPs and RSSD@NPs exhibited significantly better tumor-growth inhibition compared with that of the free DM1, QCCD@NPs or QSSD@NPs (Figure (Figure4A).4A). RSSD@NPs showed the most suppression on B16 tumor up to 25 days, and resulted in a tumor volume 4 times smaller than the saline group at the end of the experiment. The final tumor volumes in various nano-DDS groups ranked from the greatest to the least: QCCD@NPs, QSSD@NPs>DM1>RCCD@NPs>RSSD@NPs. Almost the same trends were found in terms of tumor weight and tumor size (Figures (Figures4B,4B, C). "	.
REF00028	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	34%	%	.	.	.	Patients with advanced neuroendocrine tumor.	.	.	.	.	.	Along with oral capecitabine therapy	.	"According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months."	.
REF00028	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	50.20%	%	.	.	.	Patients with advanced neuroendocrine tumor.	.	.	.	.	.	Along with oral capecitabine therapy	.	"According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months."	.
REF00028	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	6.80%	%	.	.	.	Patients with advanced neuroendocrine tumor.	.	.	.	.	.	Along with oral capecitabine therapy	.	"According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months."	.
REF00028	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	6.30%	%	.	.	.	Patients with advanced neuroendocrine tumor.	.	.	.	.	.	.	.	"According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months."	.
REF00028	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	60.90%	%	.	.	.	Patients with advanced neuroendocrine tumor.	.	.	.	.	.	.	.	"According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months."	.
REF00028	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	26.50%	%	.	.	.	Patients with advanced neuroendocrine tumor.	.	.	.	.	.	.	.	"According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months."	.
REF00028	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	48 months	months	.	.	.	Patients with advanced neuroendocrine tumor.	.	.	.	.	.	.	.	"According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months."	.
REF00028	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	48 months	months	.	.	.	Patients with advanced neuroendocrine tumor.	.	.	.	.	.	.	.	"According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months."	.
REF00027	PDC_00027	SSR positive lung neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR) + stable disease (SD)	76.50%	%	.	.	.	Patients with somatostatin-expressing neuroendocrine tumors who underwent Lu-DOTATATE PRRT; with CRHE.	.	.	.	.	.	.	.	"Following PRRT, 76.5% of patients with CRHE experienced benefit (partial response + stable disease), whereas 23.4% experienced progressive disease. Patients with CRHE showed more stable disease (P = 0.048) and less progressive disease (P = 0.046) following PRRT compared with no CRHE."	.
REF00027	PDC_00027	SSR positive lung neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	23.40%	%	.	.	.	Patients with somatostatin-expressing neuroendocrine tumors who underwent Lu-DOTATATE PRRT; with CRHE.	.	.	.	.	.	.	.	"Following PRRT, 76.5% of patients with CRHE experienced benefit (partial response + stable disease), whereas 23.4% experienced progressive disease. Patients with CRHE showed more stable disease (P = 0.048) and less progressive disease (P = 0.046) following PRRT compared with no CRHE."	.
REF00025	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Hematopoietic neoplasm	2.90%	%	.	.	.	Patients with gastroenteropancreatic neuroendocrine tumors.	.	.	.	.	.	.	.	"8 patients (2.9%) developed a hematopoietic neoplasm (4 MDS, 1 AML, 1 MPN, and 2 MDS/MPN) and 3 patients (1.1%) developed BM failure characterized by cytopenia and BM aplasia. "	.
REF00025	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Bone marrow failure rate	1.10%	%	.	.	.	Patients with gastroenteropancreatic neuroendocrine tumors.	.	.	.	.	.	.	.	"8 patients (2.9%) developed a hematopoietic neoplasm (4 MDS, 1 AML, 1 MPN, and 2 MDS/MPN) and 3 patients (1.1%) developed BM failure characterized by cytopenia and BM aplasia. "	.
REF00025	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Median latency period	41 months	months	.	.	.	Patients with gastroenteropancreatic neuroendocrine tumors.	.	.	.	.	.	.	.	"The median latency period at diagnosis (or first suspicion of a PHD) was 41 mo (range, 15-84 mo). "	.
REF00025	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Number of hematopoietic neoplasms	3	.	.	.	.	Patients with gastroenteropancreatic neuroendocrine tumors.	.	.	.	.	.	.	.	"The expected number of hematopoietic neoplasms based on The Netherlands Cancer Registry data was 3.0, resulting in a relative risk of 2.7 (95% confidence interval, 0.7-10.0). "	.
REF00025	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	.	Relative risk of hematopoietic neoplasms	2.7	.	.	.	.	Patients with gastroenteropancreatic neuroendocrine tumors.	.	.	.	.	.	.	.	"The expected number of hematopoietic neoplasms based on The Netherlands Cancer Registry data was 3.0, resulting in a relative risk of 2.7 (95% confidence interval, 0.7-10.0). "	.
REF00024	PDC_00057	Castration and taxane resistant prostate cancer	Men with histologically confirmed prostatic adenocarcinoma.	Identified from the Human Clinical Data	.	Hematologic toxicity	88%	%	.	.	.	.	.	.	.	.	.	.	.	"The most common all-grade adverse events were hematologic (22; 88%), fatigue (19; 76%), anorexia (13; 52%),alopecia(13; 52%), nausea (13; 52%), and vomiting (8;32%)."	.
REF00024	PDC_00057	Castration and taxane resistant prostate cancer	Men with histologically confirmed prostatic adenocarcinoma.	Identified from the Human Clinical Data	.	Fatigue	76%	%	.	.	.	.	.	.	.	.	.	.	.	"The most common all-grade adverse events were hematologic (22; 88%), fatigue (19; 76%), anorexia (13; 52%),alopecia(13; 52%), nausea (13; 52%), and vomiting (8;32%)."	.
REF00024	PDC_00057	Castration and taxane resistant prostate cancer	Men with histologically confirmed prostatic adenocarcinoma.	Identified from the Human Clinical Data	.	Alopecia toxicity	52.00%	%	.	.	.	.	.	.	.	.	.	.	.	"The most common all-grade adverse events were hematologic (22; 88%), fatigue (19; 76%), anorexia (13; 52%),alopecia(13; 52%), nausea (13; 52%), and vomiting (8;32%)."	.
REF00024	PDC_00057	Castration and taxane resistant prostate cancer	Men with histologically confirmed prostatic adenocarcinoma.	Identified from the Human Clinical Data	.	Nausea toxicity	52%	%	.	.	.	.	.	.	.	.	.	.	.	"The most common all-grade adverse events were hematologic (22; 88%), fatigue (19; 76%), anorexia (13; 52%),alopecia(13; 52%), nausea (13; 52%), and vomiting (8;32%)."	.
REF00024	PDC_00057	Castration and taxane resistant prostate cancer	Men with histologically confirmed prostatic adenocarcinoma.	Identified from the Human Clinical Data	.	Vomit	32%	%	.	.	.	.	.	.	.	.	.	.	.	"The most common all-grade adverse events were hematologic (22; 88%), fatigue (19; 76%), anorexia (13; 52%),alopecia(13; 52%), nausea (13; 52%), and vomiting (8;32%)."	.
REF00024	PDC_00057	Castration and taxane resistant prostate cancer	Men with histologically confirmed prostatic adenocarcinoma.	Identified from the Human Clinical Data	.	Grade &ge; 3 hematologic toxicity	56%	%	.	.	.	.	.	.	.	.	.	.	.	Fourteen of 25 patients (56%) experienced a Grade &ge; 3 hematologic toxicity	.
REF00024	PDC_00057	Castration and taxane resistant prostate cancer	Men with histologically confirmed prostatic adenocarcinoma.	Identified from the Human Clinical Data	.	Neutropenia	56%	%	.	.	.	.	.	.	.	.	.	.	.	The most common hematologic adverse event was neutropenia at 56% (all grades).	.
REF00024	PDC_00057	Castration and taxane resistant prostate cancer	Men with histologically confirmed prostatic adenocarcinoma.	Identified from the Human Clinical Data	.	Grade 3/4 nonhematologic toxicities	24%	%	.	.	.	.	.	.	.	.	.	.	.	Six of 25 patients (24%) experienced Grade 3 or 4 nonhematologic toxicities	.
REF00024	PDC_00057	Castration and taxane resistant prostate cancer	Men with histologically confirmed prostatic adenocarcinoma.	Identified from the Human Clinical Data	.	Median progression-free survival (mPFS)	3.8 months	months	.	.	.	.	.	.	.	.	.	.	.	"With a median follow-up of 16.1 months (range, 3.2-36.1), the median PFS was 3.8 months (95% confidence interval [CI], 2.1-4.4) and median OS was 6.0 months (95% CI, 4.2-10.1; Figure 3)."	.
REF00024	PDC_00057	Castration and taxane resistant prostate cancer	Men with histologically confirmed prostatic adenocarcinoma.	Identified from the Human Clinical Data	.	Median overall survival (mOS)	6.0 months	months	.	.	.	.	.	.	.	.	.	.	.	"With a median follow-up of 16.1 months (range, 3.2-36.1), the median PFS was 3.8 months (95% confidence interval [CI], 2.1-4.4) and median OS was 6.0 months (95% CI, 4.2-10.1; Figure 3)."	.
REF00023	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	>50% PSA decline	53.00%	%	.	.	.	"Patients with metastatic castration-resistant prostate cance, who had been treated with at least one next-generation antihormonal drug as well as chemotherapy."	.	.	.	.	159 cycle	Median dose 6.11 GBq	.	"A decline in prostate-specific antigen (PSA) of &ge;50% occurred in 53%, and a decline in PSA of any amount in 91% of patients. The estimated median OS was 32 weeks. "	.
REF00023	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	PSA decline	91%	%	.	.	.	"Patients with metastatic castration-resistant prostate cance, who had been treated with at least one next-generation antihormonal drug as well as chemotherapy."	.	.	.	.	159 cycle	Median dose 6.11 GBq	.	"A decline in prostate-specific antigen (PSA) of &ge;50% occurred in 53%, and a decline in PSA of any amount in 91% of patients. The estimated median OS was 32 weeks. "	.
REF00023	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Median overall survival (mOS)	32 weeks	weeks	.	.	.	"Patients with metastatic castration-resistant prostate cance, who had been treated with at least one next-generation antihormonal drug as well as chemotherapy."	.	.	.	.	159 cycle	Median dose 6.11 GBq	.	"A decline in prostate-specific antigen (PSA) of &ge;50% occurred in 53%, and a decline in PSA of any amount in 91% of patients. The estimated median OS was 32 weeks. "	.
REF00023	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	.	Median progression-free survival (mPFS)	18 weeks	weeks	.	.	.	"Patients with metastatic castration-resistant prostate cance, who had been treated with at least one next-generation antihormonal drug as well as chemotherapy."	.	.	.	.	159 cycle	Median dose 6.11 GBq	.	The median estimated PSA progression-free survival (PPFS) was 18 weeks. 	.
REF00022	PDC_00104	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	"Flow cytometry confirmed that increasing amounts of E1-3 peptide doxorubicin conjugate (3) were able to accumulate into medulloblastoma cells over a 3 h time period, with most of the doxorubicin (5) located within the nucleus (Supplementary Figure 8)."	6 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00104	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Colon adenocarcinoma	CD13-negative HT29 cell	.	"Flow cytometry confirmed that increasing amounts of E1-3 peptide doxorubicin conjugate (3) were able to accumulate into medulloblastoma cells over a 3 h time period, with most of the doxorubicin (5) located within the nucleus (Supplementary Figure 8)."	6 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00104	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	23.8 &plusmn; 0.7 &micro;M	&micro;M	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	72 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00104	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	20.6 &plusmn; 5.6 &micro;M	&micro;M	.	.	.	.	Colon adenocarcinoma	CD13-negative HT29 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	72 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00353	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.8 &plusmn; 0.7 &micro;M	&micro;M	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	6 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00353	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	19.0 &plusmn; 1.4 &micro;M	&micro;M	.	.	.	.	Colon adenocarcinoma	CD13-negative HT29 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	6 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00353	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.0 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	72 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00353	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.3 &plusmn; 0.9 &micro;M	&micro;M	.	.	.	.	Colon adenocarcinoma	CD13-negative HT29 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	72 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00354	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.0 &plusmn; 0.1 &micro;M	&micro;M	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	6 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00354	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.3 &plusmn; 2.2 &micro;M	&micro;M	.	.	.	.	Colon adenocarcinoma	CD13-negative HT29 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	6 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00354	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.3 &plusmn; 0.6 &micro;M	&micro;M	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	72 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00354	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.7 &plusmn; 0.9 &micro;M	&micro;M	.	.	.	.	Colon adenocarcinoma	CD13-negative HT29 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	72 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00355	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	45.2 &plusmn; 13.2 &micro;M	&micro;M	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	6 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00355	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Colon adenocarcinoma	CD13-negative HT29 cell	.	"Flow cytometry confirmed that increasing amounts of E1-3 peptide doxorubicin conjugate (3) were able to accumulate into medulloblastoma cells over a 3 h time period, with most of the doxorubicin (5) located within the nucleus (Supplementary Figure 8)."	6 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00355	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	14.5 &plusmn; 2.0 &micro;M	&micro;M	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	72 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00355	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Colon adenocarcinoma	CD13-negative HT29 cell	.	"Flow cytometry confirmed that increasing amounts of E1-3 peptide doxorubicin conjugate (3) were able to accumulate into medulloblastoma cells over a 3 h time period, with most of the doxorubicin (5) located within the nucleus (Supplementary Figure 8)."	72 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00356	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.7 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	6 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00356	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.7 &plusmn; 1.2 &micro;M	&micro;M	.	.	.	.	Colon adenocarcinoma	CD13-negative HT29 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	6 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00356	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.4 &plusmn; 0.1 &micro;M	&micro;M	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	72 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00356	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.0 &plusmn; 0.6 &micro;M	&micro;M	.	.	.	.	Colon adenocarcinoma	CD13-negative HT29 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	72 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00357	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	43.7 &plusmn; 4.1 &micro;M	&micro;M	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	6 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00357	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Colon adenocarcinoma	CD13-negative HT29 cell	.	"Flow cytometry confirmed that increasing amounts of E1-3 peptide doxorubicin conjugate (3) were able to accumulate into medulloblastoma cells over a 3 h time period, with most of the doxorubicin (5) located within the nucleus (Supplementary Figure 8)."	6 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00357	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.8 &plusmn; 4.4 &micro;M	&micro;M	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	"Conjugates 2 and 5 (both having 17-atom ring size in NGR peptide) showed higher accumulation after 6 h incubation than the other conjugates, in accordance with their higher activity in the cytostatic experiments. Significantly, conjugate 2, which was selective in the short term cytostatic experiments, showed higer accumulatoin in HT-1080 cells. The higher uptake of 2 compared to 5 might partly compensate its slower degradation resulting in almost similar bioactivity. Conjugate 3 showed a moderate uptake that was a bit more pronounced in HT-29 cells. We speculate that the high cytostatic effect of 3 is explained by its fast decomposition resulting in the active Dau = Aoa-Gly-OH metabolite. Conjugate 1 did not show significant cellular uptake. This observation suggests that conjugate 1 has no affinity to CD13 receptors. However, after deamidation the formed isoDGR might be recognized by RGD integrin receptor, that results in moderate cytotoxicity in both cell lines during a longer treatment. Conjugates 4 and 6 showed low cellular uptake by both types of cell during the 6 h treatment. Taking also the slow metabolite release into account, this observation explains the lack of significant cytostatic effect."	72 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00022	PDC_00357	Tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Colon adenocarcinoma	CD13-negative HT29 cell	.	"Flow cytometry confirmed that increasing amounts of E1-3 peptide doxorubicin conjugate (3) were able to accumulate into medulloblastoma cells over a 3 h time period, with most of the doxorubicin (5) located within the nucleus (Supplementary Figure 8)."	72 h	.	.	"In contrast, conjugate 2 (containing a disulfide bridge) showed preferential toxicity to HT-1080 cells in the cytostatic experiments, resulting in the highest selectivity. The antitumor effect of 2 increased in time (72 h treatment), but its selectivity decreased significantly. In comparison to conjugates 3 (thioether linkage) and 5 (amide bond), both containing free Lys in the cycle, conjugate 5 had slightly better activity against HT-1080 cells. However, the selectivity of conjugate 5 to CD13 receptors (as judged by the relative toxicity against the two cell lines) was not significant after 6 h treatment, whereas it was significantly more toxic to HT-1080 cells in the 72 h experiment. This can also be explained by its higher chemostability that results in longer exposure the cells to the unmodified NGR peptide-drug conjugate. In contrast, their analogs in which the drug molecule is connected to the side chain of Lys in the cycle (conjugates 4 and 6) were more specific but less toxic, especially in the cytotoxicity experiments. Interestingly, there was no correlation between the specificity and the chemostability of the conjugates. "	.
REF00021	PDC_00047	Melanoma	.	Revealed Based on the Cell Line Data	.	Growth inhibition rate	30%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	48 h	1 &micro;M	MTT assay	The exposure of cells to PDC resulted in significant growth inhibition at all the concentrations as compared to the drug or the peptide alone. It was observed that nearly 25-fold excess concentration of the drug is required to achieve similar cytotoxicity as obtained on exposure to PDC. The RGD peptide-CLB conjugate has also been reported to show higher growth inhibition in B16F10 cells as compared to the drug or peptide alone.24 The enhanced cytotoxic effect of PDC even at lower levels indicates clear advantage in reducing the systemic exposure and side effects of the drug. 	.
REF00021	PDC_00047	Melanoma	.	Revealed Based on the Cell Line Data	.	Growth inhibition rate	33%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	48 h	5 &micro;M	MTT assay	The exposure of cells to PDC resulted in significant growth inhibition at all the concentrations as compared to the drug or the peptide alone. It was observed that nearly 25-fold excess concentration of the drug is required to achieve similar cytotoxicity as obtained on exposure to PDC. The RGD peptide-CLB conjugate has also been reported to show higher growth inhibition in B16F10 cells as compared to the drug or peptide alone.24 The enhanced cytotoxic effect of PDC even at lower levels indicates clear advantage in reducing the systemic exposure and side effects of the drug. 	"Although RNT with <sup>177</sup>Lu-DOTATATE/PSMA is known as a novel and effective therapy option for cancer that significantly improves the quality of life and survival of patients, it may have acute or chronic side effects. Therefore, any method that can ameliorate these side effects is useful in the RNT process. For this purpose, a few clinical studies have reported that antioxidants as free radical scavengers such as amifostine and vitamins C and E can reduce radioiodine-related side effects, particularly in salivary glands in thyroid cancer patients."
REF00021	PDC_00047	Melanoma	.	Revealed Based on the Cell Line Data	.	Growth inhibition rate	40%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	48 h	10 &micro;M	MTT assay	The exposure of cells to PDC resulted in significant growth inhibition at all the concentrations as compared to the drug or the peptide alone. It was observed that nearly 25-fold excess concentration of the drug is required to achieve similar cytotoxicity as obtained on exposure to PDC. The RGD peptide-CLB conjugate has also been reported to show higher growth inhibition in B16F10 cells as compared to the drug or peptide alone.24 The enhanced cytotoxic effect of PDC even at lower levels indicates clear advantage in reducing the systemic exposure and side effects of the drug. 	.
REF00021	PDC_00047	Melanoma	.	Revealed Based on the Cell Line Data	.	Growth inhibition rate	55%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	48 h	25 &micro;M	MTT assay	The exposure of cells to PDC resulted in significant growth inhibition at all the concentrations as compared to the drug or the peptide alone. It was observed that nearly 25-fold excess concentration of the drug is required to achieve similar cytotoxicity as obtained on exposure to PDC. The RGD peptide-CLB conjugate has also been reported to show higher growth inhibition in B16F10 cells as compared to the drug or peptide alone.24 The enhanced cytotoxic effect of PDC even at lower levels indicates clear advantage in reducing the systemic exposure and side effects of the drug. 	.
REF00021	PDC_00047	Melanoma	.	Revealed Based on the Cell Line Data	.	Growth inhibition rate	75%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	48 h	50 &micro;M	MTT assay	The exposure of cells to PDC resulted in significant growth inhibition at all the concentrations as compared to the drug or the peptide alone. It was observed that nearly 25-fold excess concentration of the drug is required to achieve similar cytotoxicity as obtained on exposure to PDC. The RGD peptide-CLB conjugate has also been reported to show higher growth inhibition in B16F10 cells as compared to the drug or peptide alone.24 The enhanced cytotoxic effect of PDC even at lower levels indicates clear advantage in reducing the systemic exposure and side effects of the drug. 	.
REF00020	PDC_00027	Metastatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	13%	%	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	.	.	.	"At end-of-treatment radiological restaging, 13% of patients were found to have partial response and 64% to have stable disease; 23% of patients progressed through treatment."	.
REF00020	PDC_00027	Metastatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	64%	%	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	.	.	.	"At end-of-treatment radiological restaging, 13% of patients were found to have partial response and 64% to have stable disease; 23% of patients progressed through treatment."	.
REF00020	PDC_00027	Metastatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progressed through treatment	23%	%	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	.	.	.	"At end-of-treatment radiological restaging, 13% of patients were found to have partial response and 64% to have stable disease; 23% of patients progressed through treatment."	.
REF00020	PDC_00027	Metastatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	28 months	months	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	.	.	.	The overall estimated median time to progression from the start of treatment was 28 months.	.
REF00019	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Objective response rate (ORR)	39%	%	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	.	100 mCi (3.7 GBq) 	.	"The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26-33 months] and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). "	.
REF00019	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Stable disease (SD)	43%	%	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	.	100 mCi (3.7 GBq) 	.	"The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26-33 months] and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). "	.
REF00019	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	29 months	months	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	.	100 mCi (3.7 GBq) 	.	"The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26-33 months] and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). "	.
REF00019	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Overall survival (OS)	63 months	months	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	.	100 mCi (3.7 GBq) 	.	"The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26-33 months] and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). "	.
REF00019	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Rate of long-term toxicity	0.70%	%	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	.	100 mCi (3.7 GBq) 	.	"The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26-33 months] and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). "	.
REF00019	PDC_00027	Gastroenteropancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	.	Myelodysplastic syndrome	1.50%	%	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	.	100 mCi (3.7 GBq) 	.	"The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months [95% confidence interval (CI), 26-33 months] and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). "	.
REF00018	PDC_00027	Metastatic/Advanced pulmonary neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	1-year objective response rate (ORR)	94.70%	%	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	"12-16 weeks' intervals [range, 1-5 cycles; average, 4 cycles]"	150 mCi [5.55 GBq]/cycle	.	"The observed annual OS rates were as follows: 1 year: 94.7% (95% CI, 68.1%-99.2%), 2 years: 66% (95% CI, 35.5%-84.5%), 3 years: 57.7% (95% CI, 28-78.9%), and 4 years: 38.5% (95% CI, 8.1%-69.5%); median OS was 40 months with 39% (95% CI, 13.1%-64.8%). "	.
REF00018	PDC_00027	Metastatic/Advanced pulmonary neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	2-year objective response rate (ORR)	66.00%	%	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	"12-16 weeks' intervals [range, 1-5 cycles; average, 4 cycles]"	150 mCi [5.55 GBq]/cycle	.	"The observed annual OS rates were as follows: 1 year: 94.7% (95% CI, 68.1%-99.2%), 2 years: 66% (95% CI, 35.5%-84.5%), 3 years: 57.7% (95% CI, 28-78.9%), and 4 years: 38.5% (95% CI, 8.1%-69.5%); median OS was 40 months with 39% (95% CI, 13.1%-64.8%). "	.
REF00018	PDC_00027	Metastatic/Advanced pulmonary neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	3-year objective response rate (ORR)	57.70%	%	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	"12-16 weeks' intervals [range, 1-5 cycles; average, 4 cycles]"	150 mCi [5.55 GBq]/cycle	.	"The observed annual OS rates were as follows: 1 year: 94.7% (95% CI, 68.1%-99.2%), 2 years: 66% (95% CI, 35.5%-84.5%), 3 years: 57.7% (95% CI, 28-78.9%), and 4 years: 38.5% (95% CI, 8.1%-69.5%); median OS was 40 months with 39% (95% CI, 13.1%-64.8%). "	.
REF00018	PDC_00027	Metastatic/Advanced pulmonary neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	4-year objective response rate (ORR)	38.50%	%	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	"12-16 weeks' intervals [range, 1-5 cycles; average, 4 cycles]"	150 mCi [5.55 GBq]/cycle	.	"The observed annual OS rates were as follows: 1 year: 94.7% (95% CI, 68.1%-99.2%), 2 years: 66% (95% CI, 35.5%-84.5%), 3 years: 57.7% (95% CI, 28-78.9%), and 4 years: 38.5% (95% CI, 8.1%-69.5%); median OS was 40 months with 39% (95% CI, 13.1%-64.8%). "	.
REF00018	PDC_00027	Metastatic/Advanced pulmonary neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	40 months	months	.	.	.	Patients treated with Lu-DOTATATE.	.	.	.	.	"12-16 weeks' intervals [range, 1-5 cycles; average, 4 cycles]"	150 mCi [5.55 GBq]/cycle	.	"The observed annual OS rates were as follows: 1 year: 94.7% (95% CI, 68.1%-99.2%), 2 years: 66% (95% CI, 35.5%-84.5%), 3 years: 57.7% (95% CI, 28-78.9%), and 4 years: 38.5% (95% CI, 8.1%-69.5%); median OS was 40 months with 39% (95% CI, 13.1%-64.8%). "	.
REF00017	PDC_00306	Neuroblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	3.66 &plusmn; 0.77 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	.	CellTiter-Glo luminescent cell viability assay	The obtained IC50 values for 9 (6.73 &plusmn; 2.44 uM) and 10 (3.66 &plusmn; 0.77 uM) were higher than for doxorubicin (0.90 &plusmn; 0.12 uM).	.
REF00017	PDC_00306	Neuroblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	2.47 &plusmn; 0.91 &micro;M	&micro;M	.	.	.	.	Neuroblastoma	Kelly-WT cell	.	.	72 h	.	CellTiter-Glo luminescent cell viability assay	"The cytotoxic effect of the peptide-drug conjugate on Kelly-WT cells was comparable to that of 9, but not as strong as the one of the native drug. Contrary to the other utilized substances, the antiproliferative action of the bioconjugate in wild-type and drug-resistant cells was nearly the same. In comparison with doxorubicin the cytotoxicity of 10 against Kelly-ADR cells was increased by a factor of 3 according to the obtained IC50 values. Even the unmodified dimer had roughly the same cytotoxic effect on Kelly-ADR cells as doxorubicin."	.
REF00017	PDC_00306	Neuroblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	2.76 &plusmn; 0.33 &micro;M	&micro;M	.	.	.	.	Neuroblastoma	Kelly-ADR cell	.	.	72 h	.	CellTiter-Glo luminescent cell viability assay	"The cytotoxic effect of the peptide-drug conjugate on Kelly-WT cells was comparable to that of 9, but not as strong as the one of the native drug. Contrary to the other utilized substances, the antiproliferative action of the bioconjugate in wild-type and drug-resistant cells was nearly the same. In comparison with doxorubicin the cytotoxicity of 10 against Kelly-ADR cells was increased by a factor of 3 according to the obtained IC50 values. Even the unmodified dimer had roughly the same cytotoxic effect on Kelly-ADR cells as doxorubicin."	.
REF00314	0PDC_00001	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Inhibition rate	20%	%	.	.	.	.	Normal	HEK293 cell	.	.	.	"0.3,3.0 &micro;M"	LSC assay	"In this study, using the novel isotopologue ([,-3H]Nal)Lu-PSMA-617, we examined the possible interaction of PSMA-617 with ABC (BCRP, MDR1, MRP1, MRP4) and SLC transporters (MATE1, MATE2-K, OCT3, OAT1, OAT2v1, OAT3, OAT4, PEPT2). Our results do not indicate ([,-3H]Nal)Lu-PSMA-617 is an inhibitor or substrate of any of the aforementioned transporters"	"With the successful identification of the prostate-specific membrane antigen (PSMA), a frequently overexpressed target on the surface of PCa cells, the door to novel theranostic treatment modalities was opened. Throughout the past decade, a high number of novel radioligands have emerged for the diagnosis and treatment of PCa, with [<sup>177</sup>Lu]Lu-PSMA-617 as the current gold standard in compassionate use all around the globe. Most recently, [<sup>177</sup>Lu]Lu-PSMA-617 has become the very first PSMA-targeted radionuclide therapy (TNRT) against mCRPC to be approved by the Food and Drug Administration (FDA, USA), the Medicines and Healthcare products Regulatory Agency (MHRA, UK), Health Canada and the European Medical Agency (EMA, EC)."
REF00314	0PDC_00001	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Inhibition rate	20%	%	.	.	.	.	Normal	Sf9 cell	.	.	.	"0.3,3.0 &micro;M"	LSC assay	"In this study, using the novel isotopologue ([,-3H]Nal)Lu-PSMA-617, we examined the possible interaction of PSMA-617 with ABC (BCRP, MDR1, MRP1, MRP4) and SLC transporters (MATE1, MATE2-K, OCT3, OAT1, OAT2v1, OAT3, OAT4, PEPT2). Our results do not indicate ([,-3H]Nal)Lu-PSMA-617 is an inhibitor or substrate of any of the aforementioned transporters"	"With the successful identification of the prostate-specific membrane antigen (PSMA), a frequently overexpressed target on the surface of PCa cells, the door to novel theranostic treatment modalities was opened. Throughout the past decade, a high number of novel radioligands have emerged for the diagnosis and treatment of PCa, with [<sup>177</sup>Lu]Lu-PSMA-617 as the current gold standard in compassionate use all around the globe. Most recently, [<sup>177</sup>Lu]Lu-PSMA-617 has become the very first PSMA-targeted radionuclide therapy (TNRT) against mCRPC to be approved by the Food and Drug Administration (FDA, USA), the Medicines and Healthcare products Regulatory Agency (MHRA, UK), Health Canada and the European Medical Agency (EMA, EC)."
REF00314	0PDC_00001	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Rate of higher accumulation	20%	%	.	.	.	.	Normal	HEK293 cell	.	.	20 min	"0.3,3.0 &micro;M"	LSC assay	"In this study, using the novel isotopologue ([,-3H]Nal)Lu-PSMA-617, we examined the possible interaction of PSMA-617 with ABC (BCRP, MDR1, MRP1, MRP4) and SLC transporters (MATE1, MATE2-K, OCT3, OAT1, OAT2v1, OAT3, OAT4, PEPT2). Our results do not indicate ([,-3H]Nal)Lu-PSMA-617 is an inhibitor or substrate of any of the aforementioned transporters"	"With the successful identification of the prostate-specific membrane antigen (PSMA), a frequently overexpressed target on the surface of PCa cells, the door to novel theranostic treatment modalities was opened. Throughout the past decade, a high number of novel radioligands have emerged for the diagnosis and treatment of PCa, with [<sup>177</sup>Lu]Lu-PSMA-617 as the current gold standard in compassionate use all around the globe. Most recently, [<sup>177</sup>Lu]Lu-PSMA-617 has become the very first PSMA-targeted radionuclide therapy (TNRT) against mCRPC to be approved by the Food and Drug Administration (FDA, USA), the Medicines and Healthcare products Regulatory Agency (MHRA, UK), Health Canada and the European Medical Agency (EMA, EC)."
REF00314	0PDC_00001	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Rate of higher accumulation	20%	%	.	.	.	.	Normal	CHO-K1 cell	.	.	20 min	"0.3,3.0 &micro;M"	LSC assay	"In this study, using the novel isotopologue ([,-3H]Nal)Lu-PSMA-617, we examined the possible interaction of PSMA-617 with ABC (BCRP, MDR1, MRP1, MRP4) and SLC transporters (MATE1, MATE2-K, OCT3, OAT1, OAT2v1, OAT3, OAT4, PEPT2). Our results do not indicate ([,-3H]Nal)Lu-PSMA-617 is an inhibitor or substrate of any of the aforementioned transporters"	"With the successful identification of the prostate-specific membrane antigen (PSMA), a frequently overexpressed target on the surface of PCa cells, the door to novel theranostic treatment modalities was opened. Throughout the past decade, a high number of novel radioligands have emerged for the diagnosis and treatment of PCa, with [<sup>177</sup>Lu]Lu-PSMA-617 as the current gold standard in compassionate use all around the globe. Most recently, [<sup>177</sup>Lu]Lu-PSMA-617 has become the very first PSMA-targeted radionuclide therapy (TNRT) against mCRPC to be approved by the Food and Drug Administration (FDA, USA), the Medicines and Healthcare products Regulatory Agency (MHRA, UK), Health Canada and the European Medical Agency (EMA, EC)."
REF00100	PDC_00061	Severe pain	Rat model.	Obtained from the Model Organism Data	.	Maximal antinociceptive effect	46%	%	.	.	.	.	.	.	.	.	Intravenous administration 60 min	3 mg/kg	Rat tail-flick test assay	"When equimolar doses of morphine conjugated to An2 (An2-morphine; 3 mg/kg) were compared with unconjugated morphine (1 mg/kg) at the peak effect, similar levels of antinociception were observed, reaching 46% and 49.7% of MPE, respectively."	"Given the high analgesic potency of M6G, without induction of the M3G metabolite that antagonizes the analgesic effect of morphine, M6G could be a promising drug to treat moderate to severe pain. The major issue of systemic use of M6G is its poor BBB permeability. In this study, we proposed to increase the BBB penetration of M6G and morphine by conjugation to the shuttle angiopep-2 peptide (An2). Morphine and M6G were first conjugated to An2, a 19-mer peptide that crosses the BBB by low-density lipoprotein receptor-related protein 1 (LRP1) receptor-mediated transcytosis."
REF00100	PDC_00060	Severe pain	Rat model.	Obtained from the Model Organism Data	.	Maximal antinociceptive effect	34.90%	%	.	.	.	.	.	.	.	.	Intravenous administration 60 min	4 mg/kg	Rat tail-flick test assay	"Indeed, at an equimolar dose of 3 mg/kg of morphine (i.e., 12 mg/kg), An2-M6G produced a latency to tail withdrawal reaching the cutoff (i.e., 10 seconds) after 30 minutes, an effect lasting at least 3 hours. The %MPE calculated at 60 minutes after the intravenous injection of An2-M6G at 4, 8, and 12 mg/kg (equivalent to 1, 2, and 3 mg/kg of morphine and to 1.5, 3, and 4.5 mg/kg of M6G) was 34.9%, 66.2%, and 100%, respectively."	"Given the high analgesic potency of M6G, without induction of the M3G metabolite that antagonizes the analgesic effect of morphine, M6G could be a promising drug to treat moderate to severe pain. The major issue of systemic use of M6G is its poor BBB permeability. In this study, we proposed to increase the BBB penetration of M6G and morphine by conjugation to the shuttle angiopep-2 peptide (An2). Morphine and M6G were first conjugated to An2, a 19-mer peptide that crosses the BBB by low-density lipoprotein receptor-related protein 1 (LRP1) receptor-mediated transcytosis."
REF00100	PDC_00060	Severe pain	Rat model.	Obtained from the Model Organism Data	.	Maximal antinociceptive effect	66.20%	%	.	.	.	.	.	.	.	.	Intravenous administration 60 min	8 mg/kg	Rat tail-flick test assay	"Indeed, at an equimolar dose of 3 mg/kg of morphine (i.e., 12 mg/kg), An2-M6G produced a latency to tail withdrawal reaching the cutoff (i.e., 10 seconds) after 30 minutes, an effect lasting at least 3 hours. The %MPE calculated at 60 minutes after the intravenous injection of An2-M6G at 4, 8, and 12 mg/kg (equivalent to 1, 2, and 3 mg/kg of morphine and to 1.5, 3, and 4.5 mg/kg of M6G) was 34.9%, 66.2%, and 100%, respectively."	"Given the high analgesic potency of M6G, without induction of the M3G metabolite that antagonizes the analgesic effect of morphine, M6G could be a promising drug to treat moderate to severe pain. The major issue of systemic use of M6G is its poor BBB permeability. In this study, we proposed to increase the BBB penetration of M6G and morphine by conjugation to the shuttle angiopep-2 peptide (An2). Morphine and M6G were first conjugated to An2, a 19-mer peptide that crosses the BBB by low-density lipoprotein receptor-related protein 1 (LRP1) receptor-mediated transcytosis."
REF00100	PDC_00060	Severe pain	Rat model.	Obtained from the Model Organism Data	.	Maximal antinociceptive effect	100%	%	.	.	.	.	.	.	.	.	Intravenous administration 60 min	12 mg/kg	Rat tail-flick test assay	"Indeed, at an equimolar dose of 3 mg/kg of morphine (i.e., 12 mg/kg), An2-M6G produced a latency to tail withdrawal reaching the cutoff (i.e., 10 seconds) after 30 minutes, an effect lasting at least 3 hours. The %MPE calculated at 60 minutes after the intravenous injection of An2-M6G at 4, 8, and 12 mg/kg (equivalent to 1, 2, and 3 mg/kg of morphine and to 1.5, 3, and 4.5 mg/kg of M6G) was 34.9%, 66.2%, and 100%, respectively."	"Given the high analgesic potency of M6G, without induction of the M3G metabolite that antagonizes the analgesic effect of morphine, M6G could be a promising drug to treat moderate to severe pain. The major issue of systemic use of M6G is its poor BBB permeability. In this study, we proposed to increase the BBB penetration of M6G and morphine by conjugation to the shuttle angiopep-2 peptide (An2). Morphine and M6G were first conjugated to An2, a 19-mer peptide that crosses the BBB by low-density lipoprotein receptor-related protein 1 (LRP1) receptor-mediated transcytosis."
REF00100	PDC_00061	Severe pain	Male CD1 mice.	Obtained from the Model Organism Data	.	Maximal antinociceptive effect	79%	%	.	.	.	.	.	.	.	.	Intravenous administration 30 min	30 mg/kg	Hot-plate test assay	"Similar results were also obtained in the hot-plate test using male CD1 mice. Over a 2-hour period, both morphine and An2-morphine caused similar increases in hot-plate latencies. Likewise, mice receiving An2-M6G (6 mg/kg i.v.) also exhibited a sustained and superior analgesic effect compared with equimolar doses of either morphine or M6G."	"Given the high analgesic potency of M6G, without induction of the M3G metabolite that antagonizes the analgesic effect of morphine, M6G could be a promising drug to treat moderate to severe pain. The major issue of systemic use of M6G is its poor BBB permeability. In this study, we proposed to increase the BBB penetration of M6G and morphine by conjugation to the shuttle angiopep-2 peptide (An2). Morphine and M6G were first conjugated to An2, a 19-mer peptide that crosses the BBB by low-density lipoprotein receptor-related protein 1 (LRP1) receptor-mediated transcytosis."
REF00100	PDC_00060	Severe pain	Male CD1 mice.	Obtained from the Model Organism Data	.	Maximal antinociceptive effect	100%	%	.	.	.	.	.	.	.	.	Intravenous administration 30 min	6 mg/kg	Hot-plate test assay	"Similar results were also obtained in the hot-plate test using male CD1 mice. Over a 2-hour period, both morphine and An2-morphine caused similar increases in hot-plate latencies. Likewise, mice receiving An2-M6G (6 mg/kg i.v.) also exhibited a sustained and superior analgesic effect compared with equimolar doses of either morphine or M6G."	"Given the high analgesic potency of M6G, without induction of the M3G metabolite that antagonizes the analgesic effect of morphine, M6G could be a promising drug to treat moderate to severe pain. The major issue of systemic use of M6G is its poor BBB permeability. In this study, we proposed to increase the BBB penetration of M6G and morphine by conjugation to the shuttle angiopep-2 peptide (An2). Morphine and M6G were first conjugated to An2, a 19-mer peptide that crosses the BBB by low-density lipoprotein receptor-related protein 1 (LRP1) receptor-mediated transcytosis."
REF00100	PDC_00061	Severe pain	Rat model.	Obtained from the Model Organism Data	.	Maximal antinociceptive effect	79%	%	.	.	.	.	.	.	.	.	Subcutaneous administration 95 min	20 mg/kg	Rat tail-flick test assay	"We also measured the analgesic effect of An2-morphine and An2-M6G after subcutaneous injections. Despite similar MPE at the peak effect, subcutaneous injection of 20 mg/kg An2-morphine (equivalent to 5.5 mg/kg of morphine) produced an analgesic effect that was more prolonged over the time than what was observed with an equimolar dose of morphine."	"Given the high analgesic potency of M6G, without induction of the M3G metabolite that antagonizes the analgesic effect of morphine, M6G could be a promising drug to treat moderate to severe pain. The major issue of systemic use of M6G is its poor BBB permeability. In this study, we proposed to increase the BBB penetration of M6G and morphine by conjugation to the shuttle angiopep-2 peptide (An2). Morphine and M6G were first conjugated to An2, a 19-mer peptide that crosses the BBB by low-density lipoprotein receptor-related protein 1 (LRP1) receptor-mediated transcytosis."
REF00100	PDC_00060	Severe pain	Rat model.	Obtained from the Model Organism Data	.	Maximal antinociceptive effect	74%	%	.	.	.	.	.	.	.	.	Subcutaneous administration 200 min	12 mg/kg	Rat tail-flick test assay	"We also measured the analgesic effect of An2-morphine and An2-M6G after subcutaneous injections. Despite similar MPE at the peak effect, subcutaneous injection of 20 mg/kg An2-morphine (equivalent to 5.5 mg/kg of morphine) produced an analgesic effect that was more prolonged over the time than what was observed with an equimolar dose of morphine."	"Given the high analgesic potency of M6G, without induction of the M3G metabolite that antagonizes the analgesic effect of morphine, M6G could be a promising drug to treat moderate to severe pain. The major issue of systemic use of M6G is its poor BBB permeability. In this study, we proposed to increase the BBB penetration of M6G and morphine by conjugation to the shuttle angiopep-2 peptide (An2). Morphine and M6G were first conjugated to An2, a 19-mer peptide that crosses the BBB by low-density lipoprotein receptor-related protein 1 (LRP1) receptor-mediated transcytosis."
REF00101	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline rate	60%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	6.7 day	.	2-cycles of 177lu-psma-rlt	3.5-7.5 GBq	.	"Im Median erhielten die Patienten 2 Zyklen der <sup>177</sup>Lu-PSMA-RLT. Die Mehrheit der Patienten erhielt 3,5-7,5 GBq (im Median 6,0 GBq) Aktivitt pro Zyklus. ber den gesamten Beobachtungszeitraum zeigten 45 % der Patienten eine PSA50. Irgendein PSA-Abfall trat bei 60 % der Patienten auf. (The patients received a median of 2 cycles of <sup>177</sup>Lu-PSMA-RLT. The majority of the patients received 3.5-7.5 GBq (a median of 6.0 GBq) of activity per cycle. Throughout the entire observation period, 45% of the patients exhibited a PSA50. Some decrease in PSA levels occurred in 60% of the patients.)"	"Entwickelt im Deutschen Krebsforschungszentrum in Heidelberg, ist PSMA-617 der weltweit weiterhin am hufigsten eingesetzte Ligand zur Behandlung von Patienten mit metastasiertem Prostatakarzinom. (Developed at the German Cancer Research Center in Heidelberg, PSMA-617 remains the most commonly used ligand worldwide for treating patients with metastatic prostate cancer.)"
REF00101	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	45.00%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	6.7 day	.	2-cycles of 177lu-psma-rlt	3.5-7.5 GBq	.	"Im Median erhielten die Patienten 2 Zyklen der <sup>177</sup>Lu-PSMA-RLT. Die Mehrheit der Patienten erhielt 3,5-7,5 GBq (im Median 6,0 GBq) Aktivitt pro Zyklus. ber den gesamten Beobachtungszeitraum zeigten 45 % der Patienten eine PSA50. Irgendein PSA-Abfall trat bei 60 % der Patienten auf. (The patients received a median of 2 cycles of <sup>177</sup>Lu-PSMA-RLT. The majority of the patients received 3.5-7.5 GBq (a median of 6.0 GBq) of activity per cycle. Throughout the entire observation period, 45% of the patients exhibited a PSA50. Some decrease in PSA levels occurred in 60% of the patients.)"	"Entwickelt im Deutschen Krebsforschungszentrum in Heidelberg, ist PSMA-617 der weltweit weiterhin am hufigsten eingesetzte Ligand zur Behandlung von Patienten mit metastasiertem Prostatakarzinom. (Developed at the German Cancer Research Center in Heidelberg, PSMA-617 remains the most commonly used ligand worldwide for treating patients with metastatic prostate cancer.)"
REF00102	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	&ge;10% PSA decline	58%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	At least one course of [177lu]-psma-617	6-7 GBq	.	"A subjective clinical benefit, based on the clinical evaluation by the treating oncologist, was observed in 28 patients (52%). The first PSA was measured following a median of 1.2 months from the start of treatment (range 0.4-3.7 months). PSA nadir was achieved within a median of 1.4 months (range 0.4-13.4). A maximal PSA decline of at least 20% was observed in 26 patients (50%), a maximal PSA decline of at least 50% was observed in 18 patients (35%), and a maximal PSA decline of at least 90% was observed in 7 patients (16%). Thirty patients (58%) had any PSA decline (PSA decline greater than 10%) upon their first PSA assessment."	"[<sup>177</sup>Lu]-PSMA-617 is a novel treatment modality for prostate cancer, utilizing the tumors expression of PSMA as a target to allow for the administration of mixed beta-gamma radiation directly to the site of active metastases."
REF00102	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>20% PSA decline	50.00%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	At least one course of [177lu]-psma-617	6-7 GBq	.	"A subjective clinical benefit, based on the clinical evaluation by the treating oncologist, was observed in 28 patients (52%). The first PSA was measured following a median of 1.2 months from the start of treatment (range 0.4-3.7 months). PSA nadir was achieved within a median of 1.4 months (range 0.4-13.4). A maximal PSA decline of at least 20% was observed in 26 patients (50%), a maximal PSA decline of at least 50% was observed in 18 patients (35%), and a maximal PSA decline of at least 90% was observed in 7 patients (16%). Thirty patients (58%) had any PSA decline (PSA decline greater than 10%) upon their first PSA assessment."	"[<sup>177</sup>Lu]-PSMA-617 is a novel treatment modality for prostate cancer, utilizing the tumors expression of PSMA as a target to allow for the administration of mixed beta-gamma radiation directly to the site of active metastases."
REF00102	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	35.00%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	At least one course of [177lu]-psma-617	6-7 GBq	.	"A subjective clinical benefit, based on the clinical evaluation by the treating oncologist, was observed in 28 patients (52%). The first PSA was measured following a median of 1.2 months from the start of treatment (range 0.4-3.7 months). PSA nadir was achieved within a median of 1.4 months (range 0.4-13.4). A maximal PSA decline of at least 20% was observed in 26 patients (50%), a maximal PSA decline of at least 50% was observed in 18 patients (35%), and a maximal PSA decline of at least 90% was observed in 7 patients (16%). Thirty patients (58%) had any PSA decline (PSA decline greater than 10%) upon their first PSA assessment."	"[<sup>177</sup>Lu]-PSMA-617 is a novel treatment modality for prostate cancer, utilizing the tumors expression of PSMA as a target to allow for the administration of mixed beta-gamma radiation directly to the site of active metastases."
REF00102	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>90% PSA decline	16.00%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer.	.	.	.	.	At least one course of [177lu]-psma-617	6-7 GBq	.	"A subjective clinical benefit, based on the clinical evaluation by the treating oncologist, was observed in 28 patients (52%). The first PSA was measured following a median of 1.2 months from the start of treatment (range 0.4-3.7 months). PSA nadir was achieved within a median of 1.4 months (range 0.4-13.4). A maximal PSA decline of at least 20% was observed in 26 patients (50%), a maximal PSA decline of at least 50% was observed in 18 patients (35%), and a maximal PSA decline of at least 90% was observed in 7 patients (16%). Thirty patients (58%) had any PSA decline (PSA decline greater than 10%) upon their first PSA assessment."	"[<sup>177</sup>Lu]-PSMA-617 is a novel treatment modality for prostate cancer, utilizing the tumors expression of PSMA as a target to allow for the administration of mixed beta-gamma radiation directly to the site of active metastases."
REF00103	PDC_00027	Sinonasal neuroendocrine carcinomas	A 52-year-old man with SNC.	Identified from the Human Clinical Data	High Expreesion	Resolution rate	100%	%	.	.	.	.	.	.	.	.	.	&tilde;7.4 GBq [200 mCi]	.	"On follow-up for a second PRRT cycle, there was a complete symptomatic response. Follow-up scans showed a significant decrease in the size of the sinonasal mass (&tilde;1.9 0.8 cm vs. 7.0 4.6 5.0 cm at baseline), with a significant decrease in the size of the left cervical level II lymph node (1.5 1.1 cm vs. 2.2 1.3 cm at baseline) and complete resolution of the right hilar lymph node."	.
REF00104	PDC_00027	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Frequency of N0	61%	%	.	.	.	24 patients with morphologically WD-PanNETs who underwent PRRT preoperatively.	.	.	.	.	A median of 6 months (interquartile range [iqr] 6; 8 months) from the last cycle of prrt	.	Stained with hematoxylin and eosin (H&E) & Formalin-fixed and paraffin-embedded (FFPE) assay	"Patients who underwent PRRT had a trend towards a higher frequency of N0 as compared to control group (61% vs 33%, p = 0.059)."	.
REF00104	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Frequency of N0	61%	%	.	.	.	24 patients with morphologically WD-PanNETs who underwent PRRT preoperatively.	.	.	.	.	A median of 6 months (interquartile range [iqr] 6; 8 months) from the last cycle of prrt	.	Stained with hematoxylin and eosin (H&E) & Formalin-fixed and paraffin-embedded (FFPE) assay	"Patients who underwent PRRT had a trend towards a higher frequency of N0 as compared to control group (61% vs 33%, p = 0.059)."	.
REF00104	PDC_00027	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median stroma percentage	40%	%	.	.	.	24 patients with morphologically WD-PanNETs who underwent PRRT preoperatively.	.	.	.	.	A median of 6 months (interquartile range [iqr] 6; 8 months) from the last cycle of prrt	.	Stained with hematoxylin and eosin (H&E) & Formalin-fixed and paraffin-embedded (FFPE) assay	"In the PRRT group, the median stroma percentage was 40% compared to 20% in the control group (p < 0.0001)."	.
REF00104	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median stroma percentage	40%	%	.	.	.	24 patients with morphologically WD-PanNETs who underwent PRRT preoperatively.	.	.	.	.	A median of 6 months (interquartile range [iqr] 6; 8 months) from the last cycle of prrt	.	Stained with hematoxylin and eosin (H&E) & Formalin-fixed and paraffin-embedded (FFPE) assay	"In the PRRT group, the median stroma percentage was 40% compared to 20% in the control group (p < 0.0001)."	.
REF00104	PDC_00027	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	7 mm reduction in tumor diameter	mm	.	.	.	24 patients with morphologically WD-PanNETs who underwent PRRT preoperatively.	.	.	.	.	A median of 6 months (interquartile range [iqr] 6; 8 months) from the last cycle of prrt	.	Stained with hematoxylin and eosin (H&E) & Formalin-fixed and paraffin-embedded (FFPE) assay	"In the neoadjuvant group, the average reduction in tumor diameter, before and after PRRT, assessed by computerized tomography (CT), was 7 mm. The average volume reduction showed a statistically significant correlation (p < 0.022) with the percentage of stroma after PRRT."	.
REF00104	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	7 mm reduction in tumor diameter	mm	.	.	.	24 patients with morphologically WD-PanNETs who underwent PRRT preoperatively.	.	.	.	.	A median of 6 months (interquartile range [iqr] 6; 8 months) from the last cycle of prrt	.	Stained with hematoxylin and eosin (H&E) & Formalin-fixed and paraffin-embedded (FFPE) assay	"In the neoadjuvant group, the average reduction in tumor diameter, before and after PRRT, assessed by computerized tomography (CT), was 7 mm. The average volume reduction showed a statistically significant correlation (p < 0.022) with the percentage of stroma after PRRT."	.
REF00105	PDC_00027	Advanced medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Rate of calcitonin reduction	60%	%	.	.	.	8 patients with advanced medullary thyroid cancer.	.	.	.	.	From days 0 to 14 of each prrt cycle	20.9 GBq (interquartile range 8.9-27.7 GBq)	.	"Biochemical response with reduction in serum calcitonin levels was observed in 3/5 (60%) patients. With the exception of grade 2 anaemia in one patient, no other significant toxicity was observed in this cohort."	.
REF00106	PDC_00027	Carcinoid heart valve disease	.	Identified from the Human Clinical Data	High Expreesion	Rate of death decrease	46%	%	.	.	.	8 patients with histologically confirmed grade 1 or 2 NEN and echocardiographically proven carcinoid syndrome.	.	.	.	.	Four prrt infusions at 8-16 weeks intervals	7.4 GBq	.	"Patients with inoperable gastrointestinal NENs treated in the phase 3 trial of Lu-177-DOtatate for midgut neuroendocrine tumours study were found to have significantly improved survival with the use of lutetium-177 therapy versus somatostatin receptor analogues (SSRA) alone, with a reduced risk of death (46%) in the lutetium group."	"Peptide receptor radionuclide therapy (PRRT) uses lutetium-177 oxodotreotide, a radio-labelled peptide with high affinity for somatostatin receptor subtype 2. It is indicated in well-differentiated NENs that are either metastatic or surgically unsuitable that have proven somatostatin receptor positivity on imaging. Safe administration protocol requires the concomitant infusion of one litre of intravenous peptides."
REF00107	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median hepatic progression-free survival	5.7 months	months	.	.	.	28 patients with consecutive metastatic castration-resistant prostate cancer.	.	.	.	.	4-6 cycles at 6 &plusmn; 2-week intervals	6.5 &plusmn; 0.5 GBq	PET/CT assay	"Median (minimum-maximum) follow-up was 37.5 (2.3-50.6) months. In liver metastases, complete or partial response was observed in 6 patients (21%) each, and stable disease in 1 (4%), for hepatic disease control in 46%. Overall, median (95% confidence interval) PFShep was 5.7 (2.2-9.2) months, and OS, 11.7 (3.0-20.4) months. Patients with hepatic disease control did not reach the median OS, while those with hepatic progressive disease had median OS (95% confidence interval) of 6.4 (1.6-11.1) months. In multivariate analysis, hepatic disease control by <sup>177</sup>Lu-PSMA-617 RLT was significantly independently associated with OS, as was a prostate-specific antigen decline of &ge; 50% after 2 RLT cycles, and good baseline performance status (Eastern Cooperative Oncology Group 0-1). Hepatic tumor burden (&le; 25% vs. > 25% of liver volume) had no apparent relationship with hepatic tumor response, PFShep, or OS."	"Recently, several studies demonstrated promising results of <sup>177</sup>Lu-labeled prostate-specific membrane antigen radioligand therapy (<sup>177</sup>Lu-PSMA RLT) in late-stage/end-stage mCRPC. However, little is known about this modalitys efficacy specifically against liver metastases in this setting."
REF00108	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	76%	%	.	.	.	30 patients with proven metastatic castration-resistant prostate cancer.	.	.	.	.	5 cycles of treatment with 177lu-psma-617 prlt	4.94 &plusmn; 0.45 GBq/cycle	.	"After the first cycle of <sup>177</sup>Lu-PSMA-617 therapy, 9 patients expired due to their progressive disease. Of the 21 patients, where prostate-specific antigen (PSA) data are available, 16 (76%) showed reduction in PSA levels."	.
REF00108	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Reduction in liver lesion volume	99%	%	.	.	.	30 patients with proven metastatic castration-resistant prostate cancer.	.	.	.	.	5 cycles of treatment with 177lu-psma-617 prlt	4.94 &plusmn; 0.45 GBq/cycle	68Ga-PSMA-11 PET-CT assay	"The response of <sup>177</sup>Lu-PSMA-617 therapy in one of the study patients, which was evaluated by comparing the 68Ga-PSMA-11 PET-CT recorded before each therapy cycle, and from this figure, it is evident that there is drastic reduction (99%) in liver lesion volume after four treatment cycles."	.
REF00109	PDC_00158	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.093 &plusmn; 0.014 nM	nM	.	.	.	.	.	.	11.2 h	.	.	.	GLP-1 receptor cAMP activity study	"Lys20-derived conjugates 1a-c retained EC50 values in low subnanomolar range (0.093-0.28 nM). However, Lys28- (1d-f) and Lys30- (1g-i) derived conjugates seemed to be more negatively affected by GFZ modification, showing EC50 values of 0.21-0.84 nM and 0.38-1.32 nM respectively."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00159	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.12 &plusmn; 0.02 nM	nM	.	.	.	.	.	.	14.2 h	.	.	.	GLP-1 receptor cAMP activity study	"Lys20-derived conjugates 1a-c retained EC50 values in low subnanomolar range (0.093-0.28 nM). However, Lys28- (1d-f) and Lys30- (1g-i) derived conjugates seemed to be more negatively affected by GFZ modification, showing EC50 values of 0.21-0.84 nM and 0.38-1.32 nM respectively."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00160	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.28 &plusmn; 0.06 nM	nM	.	.	.	.	.	.	18.1 h	.	.	.	GLP-1 receptor cAMP activity study	"Lys20-derived conjugates 1a-c retained EC50 values in low subnanomolar range (0.093-0.28 nM). However, Lys28- (1d-f) and Lys30- (1g-i) derived conjugates seemed to be more negatively affected by GFZ modification, showing EC50 values of 0.21-0.84 nM and 0.38-1.32 nM respectively."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00161	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.21 &plusmn; 0.06 nM	nM	.	.	.	.	.	.	10.1 h	.	.	.	GLP-1 receptor cAMP activity study	"Lys20-derived conjugates 1a-c retained EC50 values in low subnanomolar range (0.093-0.28 nM). However, Lys28- (1d-f) and Lys30- (1g-i) derived conjugates seemed to be more negatively affected by GFZ modification, showing EC50 values of 0.21-0.84 nM and 0.38-1.32 nM respectively."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00162	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.39 &plusmn; 0.12 nM	nM	.	.	.	.	.	.	13.3 h	.	.	.	GLP-1 receptor cAMP activity study	"Lys20-derived conjugates 1a-c retained EC50 values in low subnanomolar range (0.093-0.28 nM). However, Lys28- (1d-f) and Lys30- (1g-i) derived conjugates seemed to be more negatively affected by GFZ modification, showing EC50 values of 0.21-0.84 nM and 0.38-1.32 nM respectively."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00163	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.84 &plusmn; 0.32 nM	nM	.	.	.	.	.	.	17.4 h	.	.	.	GLP-1 receptor cAMP activity study	"Lys20-derived conjugates 1a-c retained EC50 values in low subnanomolar range (0.093-0.28 nM). However, Lys28- (1d-f) and Lys30- (1g-i) derived conjugates seemed to be more negatively affected by GFZ modification, showing EC50 values of 0.21-0.84 nM and 0.38-1.32 nM respectively."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00164	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.38 &plusmn; 0.06 nM	nM	.	.	.	.	.	.	10.7 h	.	.	.	GLP-1 receptor cAMP activity study	"Lys20-derived conjugates 1a-c retained EC50 values in low subnanomolar range (0.093-0.28 nM). However, Lys28- (1d-f) and Lys30- (1g-i) derived conjugates seemed to be more negatively affected by GFZ modification, showing EC50 values of 0.21-0.84 nM and 0.38-1.32 nM respectively."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00165	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.69 &plusmn; 0.25 nM	nM	.	.	.	.	.	.	13.1 h	.	.	.	GLP-1 receptor cAMP activity study	"Lys20-derived conjugates 1a-c retained EC50 values in low subnanomolar range (0.093-0.28 nM). However, Lys28- (1d-f) and Lys30- (1g-i) derived conjugates seemed to be more negatively affected by GFZ modification, showing EC50 values of 0.21-0.84 nM and 0.38-1.32 nM respectively."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00166	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	1.32 &plusmn; 0.42 nM	nM	.	.	.	.	.	.	16.7 h	.	.	.	GLP-1 receptor cAMP activity study	"Lys20-derived conjugates 1a-c retained EC50 values in low subnanomolar range (0.093-0.28 nM). However, Lys28- (1d-f) and Lys30- (1g-i) derived conjugates seemed to be more negatively affected by GFZ modification, showing EC50 values of 0.21-0.84 nM and 0.38-1.32 nM respectively."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00158	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Area under the curve (AUC)	600	.	.	.	.	.	.	.	11.2 h	.	120 min	.	LC-MS/MS assay	"Next, the hypoglycemic effects of 1a-i were tested in ICR mice to investigate their in vivo GLP-1 receptor activation activity. As illustrated in Fig. 2C-F, 1a-i significantly blunted OGTT-evoked blood glucose concentration increase, in a similar manner to GLP-1 and xGLP-1. In line with the in vitro results, conjugates 1a-c exhibited superior in vivo hypoglycemic activity to 1d-f and 1g-i. The stabilities of 1a-i was tested by incubating them with rat plasma over 48 h at 37 C and monitoring the intact compounds using LC-MS/MS. To our delight, GFZ conjugation remarkably improved the stabilities of 1a-i as compared with GLP-1 and xGLP-1. In accordance with the results from our previous studies, a positive correlation between the length of alkyl chain linker and plasma half-life was clearly observed, while the conjugation site had little impact. Taken together, Lys20-derived conjugates 1b and 1c were selected for the next round optimization with a collective consideration of their in vitro GLP-1 receptor activation potency, in vivo glucose-lowering activity, and plasma stability."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00159	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Area under the curve (AUC)	650	.	.	.	.	.	.	.	14.2 h	.	120 min	.	LC-MS/MS assay	"Next, the hypoglycemic effects of 1a-i were tested in ICR mice to investigate their in vivo GLP-1 receptor activation activity. As illustrated in Fig. 2C-F, 1a-i significantly blunted OGTT-evoked blood glucose concentration increase, in a similar manner to GLP-1 and xGLP-1. In line with the in vitro results, conjugates 1a-c exhibited superior in vivo hypoglycemic activity to 1d-f and 1g-i. The stabilities of 1a-i was tested by incubating them with rat plasma over 48 h at 37 C and monitoring the intact compounds using LC-MS/MS. To our delight, GFZ conjugation remarkably improved the stabilities of 1a-i as compared with GLP-1 and xGLP-1. In accordance with the results from our previous studies, a positive correlation between the length of alkyl chain linker and plasma half-life was clearly observed, while the conjugation site had little impact. Taken together, Lys20-derived conjugates 1b and 1c were selected for the next round optimization with a collective consideration of their in vitro GLP-1 receptor activation potency, in vivo glucose-lowering activity, and plasma stability."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00160	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Area under the curve (AUC)	650	.	.	.	.	.	.	.	18.1 h	.	120 min	.	LC-MS/MS assay	"Next, the hypoglycemic effects of 1a-i were tested in ICR mice to investigate their in vivo GLP-1 receptor activation activity. As illustrated in Fig. 2C-F, 1a-i significantly blunted OGTT-evoked blood glucose concentration increase, in a similar manner to GLP-1 and xGLP-1. In line with the in vitro results, conjugates 1a-c exhibited superior in vivo hypoglycemic activity to 1d-f and 1g-i. The stabilities of 1a-i was tested by incubating them with rat plasma over 48 h at 37 C and monitoring the intact compounds using LC-MS/MS. To our delight, GFZ conjugation remarkably improved the stabilities of 1a-i as compared with GLP-1 and xGLP-1. In accordance with the results from our previous studies, a positive correlation between the length of alkyl chain linker and plasma half-life was clearly observed, while the conjugation site had little impact. Taken together, Lys20-derived conjugates 1b and 1c were selected for the next round optimization with a collective consideration of their in vitro GLP-1 receptor activation potency, in vivo glucose-lowering activity, and plasma stability."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00161	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Area under the curve (AUC)	650	.	.	.	.	.	.	.	10.1 h	.	120 min	.	LC-MS/MS assay	"Next, the hypoglycemic effects of 1a-i were tested in ICR mice to investigate their in vivo GLP-1 receptor activation activity. As illustrated in Fig. 2C-F, 1a-i significantly blunted OGTT-evoked blood glucose concentration increase, in a similar manner to GLP-1 and xGLP-1. In line with the in vitro results, conjugates 1a-c exhibited superior in vivo hypoglycemic activity to 1d-f and 1g-i. The stabilities of 1a-i was tested by incubating them with rat plasma over 48 h at 37 C and monitoring the intact compounds using LC-MS/MS. To our delight, GFZ conjugation remarkably improved the stabilities of 1a-i as compared with GLP-1 and xGLP-1. In accordance with the results from our previous studies, a positive correlation between the length of alkyl chain linker and plasma half-life was clearly observed, while the conjugation site had little impact. Taken together, Lys20-derived conjugates 1b and 1c were selected for the next round optimization with a collective consideration of their in vitro GLP-1 receptor activation potency, in vivo glucose-lowering activity, and plasma stability."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00162	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Area under the curve (AUC)	700	.	.	.	.	.	.	.	13.3 h	.	120 min	.	LC-MS/MS assay	"Next, the hypoglycemic effects of 1a-i were tested in ICR mice to investigate their in vivo GLP-1 receptor activation activity. As illustrated in Fig. 2C-F, 1a-i significantly blunted OGTT-evoked blood glucose concentration increase, in a similar manner to GLP-1 and xGLP-1. In line with the in vitro results, conjugates 1a-c exhibited superior in vivo hypoglycemic activity to 1d-f and 1g-i. The stabilities of 1a-i was tested by incubating them with rat plasma over 48 h at 37 C and monitoring the intact compounds using LC-MS/MS. To our delight, GFZ conjugation remarkably improved the stabilities of 1a-i as compared with GLP-1 and xGLP-1. In accordance with the results from our previous studies, a positive correlation between the length of alkyl chain linker and plasma half-life was clearly observed, while the conjugation site had little impact. Taken together, Lys20-derived conjugates 1b and 1c were selected for the next round optimization with a collective consideration of their in vitro GLP-1 receptor activation potency, in vivo glucose-lowering activity, and plasma stability."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00167	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.083 nM	nM	.	.	.	.	.	.	17.2 h	.	.	.	GLP-1 receptor cAMP activity study	"The same biological tests as described in section 3.2 were applied to evaluate 2a-d. As shown in Fig. 3B, C-terminal optimization decreased the EC50 values of 1b and 1c. Compounds 2c and 2d (EC50 = 0.053 and 0.11 nM, respectively) with a lixisenatide-like C-terminus showed higher receptor activation potency than exendin-4-like C-terminus counterparts 2a and 2b (EC50 = 0.083 and 0.14 nM, respectively). In vivo glucose-lowering studies indicated that 2a-d had similar hypoglycemic activity to xGLP-1."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00168	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.14 nM	nM	.	.	.	.	.	.	21.4 h	.	.	.	GLP-1 receptor cAMP activity study	"The same biological tests as described in section 3.2 were applied to evaluate 2a-d. As shown in Fig. 3B, C-terminal optimization decreased the EC50 values of 1b and 1c. Compounds 2c and 2d (EC50 = 0.053 and 0.11 nM, respectively) with a lixisenatide-like C-terminus showed higher receptor activation potency than exendin-4-like C-terminus counterparts 2a and 2b (EC50 = 0.083 and 0.14 nM, respectively). In vivo glucose-lowering studies indicated that 2a-d had similar hypoglycemic activity to xGLP-1."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00169	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.053 nM	nM	.	.	.	.	.	.	16.3 h	.	.	.	GLP-1 receptor cAMP activity study	"The same biological tests as described in section 3.2 were applied to evaluate 2a-d. As shown in Fig. 3B, C-terminal optimization decreased the EC50 values of 1b and 1c. Compounds 2c and 2d (EC50 = 0.053 and 0.11 nM, respectively) with a lixisenatide-like C-terminus showed higher receptor activation potency than exendin-4-like C-terminus counterparts 2a and 2b (EC50 = 0.083 and 0.14 nM, respectively). In vivo glucose-lowering studies indicated that 2a-d had similar hypoglycemic activity to xGLP-1."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00170	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.11 nM	nM	.	.	.	.	.	.	20.1 h	.	.	.	GLP-1 receptor cAMP activity study	"The same biological tests as described in section 3.2 were applied to evaluate 2a-d. As shown in Fig. 3B, C-terminal optimization decreased the EC50 values of 1b and 1c. Compounds 2c and 2d (EC50 = 0.053 and 0.11 nM, respectively) with a lixisenatide-like C-terminus showed higher receptor activation potency than exendin-4-like C-terminus counterparts 2a and 2b (EC50 = 0.083 and 0.14 nM, respectively). In vivo glucose-lowering studies indicated that 2a-d had similar hypoglycemic activity to xGLP-1."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00167	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Area under the curve (AUC)	780	.	.	.	.	.	.	.	17.2 h	.	120 min	.	LC-MS/MS assay	"The same biological tests as described in section 3.2 were applied to evaluate 2a-d. As shown in Fig. 3B, C-terminal optimization decreased the EC50 values of 1b and 1c. Compounds 2c and 2d (EC50 = 0.053 and 0.11 nM, respectively) with a lixisenatide-like C-terminus showed higher receptor activation potency than exendin-4-like C-terminus counterparts 2a and 2b (EC50 = 0.083 and 0.14 nM, respectively). In vivo glucose-lowering studies indicated that 2a-d had similar hypoglycemic activity to xGLP-1."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00168	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Area under the curve (AUC)	820	.	.	.	.	.	.	.	21.4 h	.	120 min	.	LC-MS/MS assay	"The same biological tests as described in section 3.2 were applied to evaluate 2a-d. As shown in Fig. 3B, C-terminal optimization decreased the EC50 values of 1b and 1c. Compounds 2c and 2d (EC50 = 0.053 and 0.11 nM, respectively) with a lixisenatide-like C-terminus showed higher receptor activation potency than exendin-4-like C-terminus counterparts 2a and 2b (EC50 = 0.083 and 0.14 nM, respectively). In vivo glucose-lowering studies indicated that 2a-d had similar hypoglycemic activity to xGLP-1."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00169	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Area under the curve (AUC)	750	.	.	.	.	.	.	.	16.3 h	.	120 min	.	LC-MS/MS assay	"The same biological tests as described in section 3.2 were applied to evaluate 2a-d. As shown in Fig. 3B, C-terminal optimization decreased the EC50 values of 1b and 1c. Compounds 2c and 2d (EC50 = 0.053 and 0.11 nM, respectively) with a lixisenatide-like C-terminus showed higher receptor activation potency than exendin-4-like C-terminus counterparts 2a and 2b (EC50 = 0.083 and 0.14 nM, respectively). In vivo glucose-lowering studies indicated that 2a-d had similar hypoglycemic activity to xGLP-1."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00170	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Area under the curve (AUC)	800	.	.	.	.	.	.	.	20.1 h	.	120 min	.	LC-MS/MS assay	"The same biological tests as described in section 3.2 were applied to evaluate 2a-d. As shown in Fig. 3B, C-terminal optimization decreased the EC50 values of 1b and 1c. Compounds 2c and 2d (EC50 = 0.053 and 0.11 nM, respectively) with a lixisenatide-like C-terminus showed higher receptor activation potency than exendin-4-like C-terminus counterparts 2a and 2b (EC50 = 0.083 and 0.14 nM, respectively). In vivo glucose-lowering studies indicated that 2a-d had similar hypoglycemic activity to xGLP-1."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00171	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.11 &plusmn; 0.03 nM	nM	.	.	.	.	.	.	30.4 h	.	.	.	GLP-1 receptor cAMP activity study	"The receptor activation potency and in vivo hypoglycemic activities of 3a-d were further investigated. It was found that dimeric-GFZ modification resulted in slightly reduced receptor activation potency of 3a (EC50 = 0.11 &plusmn; 0.03 nM), 3b (EC50 = 0.17 &plusmn; 0.05 nM), 3c (EC50 = 0.091 &plusmn; 0.026 nM), and 3d (EC50 = 0.31 &plusmn; 0.06 nM) as compared with that of 2a-d."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00172	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.17 &plusmn; 0.05 nM	nM	.	.	.	.	.	.	37.6 h	.	.	.	GLP-1 receptor cAMP activity study	"The receptor activation potency and in vivo hypoglycemic activities of 3a-d were further investigated. It was found that dimeric-GFZ modification resulted in slightly reduced receptor activation potency of 3a (EC50 = 0.11 &plusmn; 0.03 nM), 3b (EC50 = 0.17 &plusmn; 0.05 nM), 3c (EC50 = 0.091 &plusmn; 0.026 nM), and 3d (EC50 = 0.31 &plusmn; 0.06 nM) as compared with that of 2a-d."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00173	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.091 &plusmn; 0.026 nM	nM	.	.	.	.	.	.	29.5 h	.	.	.	GLP-1 receptor cAMP activity study	"The receptor activation potency and in vivo hypoglycemic activities of 3a-d were further investigated. It was found that dimeric-GFZ modification resulted in slightly reduced receptor activation potency of 3a (EC50 = 0.11 &plusmn; 0.03 nM), 3b (EC50 = 0.17 &plusmn; 0.05 nM), 3c (EC50 = 0.091 &plusmn; 0.026 nM), and 3d (EC50 = 0.31 &plusmn; 0.06 nM) as compared with that of 2a-d."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00174	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Half Maximal Effective Concentration (EC50)	0.31 &plusmn; 0.06 nM	nM	.	.	.	.	.	.	33.9 h	.	.	.	GLP-1 receptor cAMP activity study	"The receptor activation potency and in vivo hypoglycemic activities of 3a-d were further investigated. It was found that dimeric-GFZ modification resulted in slightly reduced receptor activation potency of 3a (EC50 = 0.11 &plusmn; 0.03 nM), 3b (EC50 = 0.17 &plusmn; 0.05 nM), 3c (EC50 = 0.091 &plusmn; 0.026 nM), and 3d (EC50 = 0.31 &plusmn; 0.06 nM) as compared with that of 2a-d."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00171	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Area under the curve (AUC)	600	.	.	.	.	.	.	.	30.4 h	.	120 min	.	LC-MS/MS assay	"In addition, 3a-c significantly reduced glucose excursion after oral glucose challenge in ICR mice, showing comparable hypoglycemic activities to the positive control liraglutide. The glucose-lowering activity of 3d was lower than liraglutide and 3a-c in ICR mice. Furthermore, hypoglycemic duration tests were conducted on a well-known type 2 diabetic model (db/db mice) to examine the glucose-lowering behaviors of 3a-c. As shown in Figs. 5D, 3a-c treatments reached a similar nadir of glucose level to liraglutide treatment. Particularly, 3b administration maintained the normoglycemia state in db/db mice over 24 h, showing a clearly longer hypoglycemic duration than liraglutide, which was further demonstrated from the AUCglucose values (P < 0.001)."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00172	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Area under the curve (AUC)	600	.	.	.	.	.	.	.	37.6 h	.	120 min	.	LC-MS/MS assay	"In addition, 3a-c significantly reduced glucose excursion after oral glucose challenge in ICR mice, showing comparable hypoglycemic activities to the positive control liraglutide. The glucose-lowering activity of 3d was lower than liraglutide and 3a-c in ICR mice. Furthermore, hypoglycemic duration tests were conducted on a well-known type 2 diabetic model (db/db mice) to examine the glucose-lowering behaviors of 3a-c. As shown in Figs. 5D, 3a-c treatments reached a similar nadir of glucose level to liraglutide treatment. Particularly, 3b administration maintained the normoglycemia state in db/db mice over 24 h, showing a clearly longer hypoglycemic duration than liraglutide, which was further demonstrated from the AUCglucose values (P < 0.001)."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00173	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Area under the curve (AUC)	600	.	.	.	.	.	.	.	29.5 h	.	120 min	.	LC-MS/MS assay	"In addition, 3a-c significantly reduced glucose excursion after oral glucose challenge in ICR mice, showing comparable hypoglycemic activities to the positive control liraglutide. The glucose-lowering activity of 3d was lower than liraglutide and 3a-c in ICR mice. Furthermore, hypoglycemic duration tests were conducted on a well-known type 2 diabetic model (db/db mice) to examine the glucose-lowering behaviors of 3a-c. As shown in Figs. 5D, 3a-c treatments reached a similar nadir of glucose level to liraglutide treatment. Particularly, 3b administration maintained the normoglycemia state in db/db mice over 24 h, showing a clearly longer hypoglycemic duration than liraglutide, which was further demonstrated from the AUCglucose values (P < 0.001)."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00174	Diabetes mellitus	ICR mice.	Obtained from the Model Organism Data	.	Area under the curve (AUC)	700	.	.	.	.	.	.	.	33.9 h	.	120 min	.	LC-MS/MS assay	"In addition, 3a-c significantly reduced glucose excursion after oral glucose challenge in ICR mice, showing comparable hypoglycemic activities to the positive control liraglutide. The glucose-lowering activity of 3d was lower than liraglutide and 3a-c in ICR mice. Furthermore, hypoglycemic duration tests were conducted on a well-known type 2 diabetic model (db/db mice) to examine the glucose-lowering behaviors of 3a-c. As shown in Figs. 5D, 3a-c treatments reached a similar nadir of glucose level to liraglutide treatment. Particularly, 3b administration maintained the normoglycemia state in db/db mice over 24 h, showing a clearly longer hypoglycemic duration than liraglutide, which was further demonstrated from the AUCglucose values (P < 0.001)."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00167	Diabetes mellitus	Male SD rats model.	Revealed Based on the Cell Line Data	.	Relative binding affinitt to HSA	6.8	.	.	.	.	.	.	.	17.2 h	.	.	.	HPAC assay	"The relative albumin binding abilities of 3a-d were evaluated by using HPAC. The retention factor k, calculated as k = (tR - to)/to, was used as an indicator for relative HSA affinities of tested compounds. As illustrated in Fig. 4B, the k values of 3a (k = &tilde;11.8), 3b (k = &tilde;13.3), 3c (k = &tilde;11.2), and 3d (k = &tilde;12.1) were higher than the corresponding mono-GFZ conjugates 2a (k = &tilde;6.8), 2b (k = &tilde;7.6), 2c (k = &tilde;6.4), and 2d (k = &tilde;7.3), as well as liraglutide (k = &tilde;9.7), indicating improved HSA affinities of the dimeric-GFZ conjugates 3a-d. The plasma stabilities of 3a-d were tested using the same method as described above. As shown in Fig. 4C, dimeric-GFZ modification significantly enhanced the stabilities of 2a-d. The in vitro half-lives of 3a-d reached &tilde;30.4, 37.6, 29.5, and 33.9 h, respectively, surpassing that of liraglutide (&tilde;27.7 h). Because peptides are metabolized much faster in mice than in human [46], it is reasonable to envision that 3a-d will exhibit even longer hypoglycemic effects (>1 day) in human."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00168	Diabetes mellitus	Male SD rats model.	Revealed Based on the Cell Line Data	.	Relative binding affinitt to HSA	7.6	.	.	.	.	.	.	.	21.4 h	.	.	.	HPAC assay	"The relative albumin binding abilities of 3a-d were evaluated by using HPAC. The retention factor k, calculated as k = (tR - to)/to, was used as an indicator for relative HSA affinities of tested compounds. As illustrated in Fig. 4B, the k values of 3a (k = &tilde;11.8), 3b (k = &tilde;13.3), 3c (k = &tilde;11.2), and 3d (k = &tilde;12.1) were higher than the corresponding mono-GFZ conjugates 2a (k = &tilde;6.8), 2b (k = &tilde;7.6), 2c (k = &tilde;6.4), and 2d (k = &tilde;7.3), as well as liraglutide (k = &tilde;9.7), indicating improved HSA affinities of the dimeric-GFZ conjugates 3a-d. The plasma stabilities of 3a-d were tested using the same method as described above. As shown in Fig. 4C, dimeric-GFZ modification significantly enhanced the stabilities of 2a-d. The in vitro half-lives of 3a-d reached &tilde;30.4, 37.6, 29.5, and 33.9 h, respectively, surpassing that of liraglutide (&tilde;27.7 h). Because peptides are metabolized much faster in mice than in human [46], it is reasonable to envision that 3a-d will exhibit even longer hypoglycemic effects (>1 day) in human."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00169	Diabetes mellitus	Male SD rats model.	Revealed Based on the Cell Line Data	.	Relative binding affinitt to HSA	6.4	.	.	.	.	.	.	.	16.3 h	.	.	.	HPAC assay	"The relative albumin binding abilities of 3a-d were evaluated by using HPAC. The retention factor k, calculated as k = (tR - to)/to, was used as an indicator for relative HSA affinities of tested compounds. As illustrated in Fig. 4B, the k values of 3a (k = &tilde;11.8), 3b (k = &tilde;13.3), 3c (k = &tilde;11.2), and 3d (k = &tilde;12.1) were higher than the corresponding mono-GFZ conjugates 2a (k = &tilde;6.8), 2b (k = &tilde;7.6), 2c (k = &tilde;6.4), and 2d (k = &tilde;7.3), as well as liraglutide (k = &tilde;9.7), indicating improved HSA affinities of the dimeric-GFZ conjugates 3a-d. The plasma stabilities of 3a-d were tested using the same method as described above. As shown in Fig. 4C, dimeric-GFZ modification significantly enhanced the stabilities of 2a-d. The in vitro half-lives of 3a-d reached &tilde;30.4, 37.6, 29.5, and 33.9 h, respectively, surpassing that of liraglutide (&tilde;27.7 h). Because peptides are metabolized much faster in mice than in human [46], it is reasonable to envision that 3a-d will exhibit even longer hypoglycemic effects (>1 day) in human."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00170	Diabetes mellitus	Male SD rats model.	Revealed Based on the Cell Line Data	.	Relative binding affinitt to HSA	7.3	.	.	.	.	.	.	.	20.1 h	.	.	.	HPAC assay	"The relative albumin binding abilities of 3a-d were evaluated by using HPAC. The retention factor k, calculated as k = (tR - to)/to, was used as an indicator for relative HSA affinities of tested compounds. As illustrated in Fig. 4B, the k values of 3a (k = &tilde;11.8), 3b (k = &tilde;13.3), 3c (k = &tilde;11.2), and 3d (k = &tilde;12.1) were higher than the corresponding mono-GFZ conjugates 2a (k = &tilde;6.8), 2b (k = &tilde;7.6), 2c (k = &tilde;6.4), and 2d (k = &tilde;7.3), as well as liraglutide (k = &tilde;9.7), indicating improved HSA affinities of the dimeric-GFZ conjugates 3a-d. The plasma stabilities of 3a-d were tested using the same method as described above. As shown in Fig. 4C, dimeric-GFZ modification significantly enhanced the stabilities of 2a-d. The in vitro half-lives of 3a-d reached &tilde;30.4, 37.6, 29.5, and 33.9 h, respectively, surpassing that of liraglutide (&tilde;27.7 h). Because peptides are metabolized much faster in mice than in human [46], it is reasonable to envision that 3a-d will exhibit even longer hypoglycemic effects (>1 day) in human."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00171	Diabetes mellitus	Male SD rats model.	Revealed Based on the Cell Line Data	.	Relative binding affinitt to HSA	11.8	.	.	.	.	.	.	.	30.4 h	.	.	.	HPAC assay	"The relative albumin binding abilities of 3a-d were evaluated by using HPAC. The retention factor k, calculated as k = (tR - to)/to, was used as an indicator for relative HSA affinities of tested compounds. As illustrated in Fig. 4B, the k values of 3a (k = &tilde;11.8), 3b (k = &tilde;13.3), 3c (k = &tilde;11.2), and 3d (k = &tilde;12.1) were higher than the corresponding mono-GFZ conjugates 2a (k = &tilde;6.8), 2b (k = &tilde;7.6), 2c (k = &tilde;6.4), and 2d (k = &tilde;7.3), as well as liraglutide (k = &tilde;9.7), indicating improved HSA affinities of the dimeric-GFZ conjugates 3a-d. The plasma stabilities of 3a-d were tested using the same method as described above. As shown in Fig. 4C, dimeric-GFZ modification significantly enhanced the stabilities of 2a-d. The in vitro half-lives of 3a-d reached &tilde;30.4, 37.6, 29.5, and 33.9 h, respectively, surpassing that of liraglutide (&tilde;27.7 h). Because peptides are metabolized much faster in mice than in human [46], it is reasonable to envision that 3a-d will exhibit even longer hypoglycemic effects (>1 day) in human."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00172	Diabetes mellitus	Male SD rats model.	Revealed Based on the Cell Line Data	.	Relative binding affinitt to HSA	13.3	.	.	.	.	.	.	.	37.6 h	.	.	.	HPAC assay	"The relative albumin binding abilities of 3a-d were evaluated by using HPAC. The retention factor k, calculated as k = (tR - to)/to, was used as an indicator for relative HSA affinities of tested compounds. As illustrated in Fig. 4B, the k values of 3a (k = &tilde;11.8), 3b (k = &tilde;13.3), 3c (k = &tilde;11.2), and 3d (k = &tilde;12.1) were higher than the corresponding mono-GFZ conjugates 2a (k = &tilde;6.8), 2b (k = &tilde;7.6), 2c (k = &tilde;6.4), and 2d (k = &tilde;7.3), as well as liraglutide (k = &tilde;9.7), indicating improved HSA affinities of the dimeric-GFZ conjugates 3a-d. The plasma stabilities of 3a-d were tested using the same method as described above. As shown in Fig. 4C, dimeric-GFZ modification significantly enhanced the stabilities of 2a-d. The in vitro half-lives of 3a-d reached &tilde;30.4, 37.6, 29.5, and 33.9 h, respectively, surpassing that of liraglutide (&tilde;27.7 h). Because peptides are metabolized much faster in mice than in human [46], it is reasonable to envision that 3a-d will exhibit even longer hypoglycemic effects (>1 day) in human."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00173	Diabetes mellitus	Male SD rats model.	Revealed Based on the Cell Line Data	.	Relative binding affinitt to HSA	11.2	.	.	.	.	.	.	.	29.5 h	.	.	.	HPAC assay	"The relative albumin binding abilities of 3a-d were evaluated by using HPAC. The retention factor k, calculated as k = (tR - to)/to, was used as an indicator for relative HSA affinities of tested compounds. As illustrated in Fig. 4B, the k values of 3a (k = &tilde;11.8), 3b (k = &tilde;13.3), 3c (k = &tilde;11.2), and 3d (k = &tilde;12.1) were higher than the corresponding mono-GFZ conjugates 2a (k = &tilde;6.8), 2b (k = &tilde;7.6), 2c (k = &tilde;6.4), and 2d (k = &tilde;7.3), as well as liraglutide (k = &tilde;9.7), indicating improved HSA affinities of the dimeric-GFZ conjugates 3a-d. The plasma stabilities of 3a-d were tested using the same method as described above. As shown in Fig. 4C, dimeric-GFZ modification significantly enhanced the stabilities of 2a-d. The in vitro half-lives of 3a-d reached &tilde;30.4, 37.6, 29.5, and 33.9 h, respectively, surpassing that of liraglutide (&tilde;27.7 h). Because peptides are metabolized much faster in mice than in human [46], it is reasonable to envision that 3a-d will exhibit even longer hypoglycemic effects (>1 day) in human."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00109	PDC_00174	Diabetes mellitus	Male SD rats model.	Revealed Based on the Cell Line Data	.	Relative binding affinitt to HSA	12.1	.	.	.	.	.	.	.	33.9 h	.	.	.	HPAC assay	"The relative albumin binding abilities of 3a-d were evaluated by using HPAC. The retention factor k, calculated as k = (tR - to)/to, was used as an indicator for relative HSA affinities of tested compounds. As illustrated in Fig. 4B, the k values of 3a (k = &tilde;11.8), 3b (k = &tilde;13.3), 3c (k = &tilde;11.2), and 3d (k = &tilde;12.1) were higher than the corresponding mono-GFZ conjugates 2a (k = &tilde;6.8), 2b (k = &tilde;7.6), 2c (k = &tilde;6.4), and 2d (k = &tilde;7.3), as well as liraglutide (k = &tilde;9.7), indicating improved HSA affinities of the dimeric-GFZ conjugates 3a-d. The plasma stabilities of 3a-d were tested using the same method as described above. As shown in Fig. 4C, dimeric-GFZ modification significantly enhanced the stabilities of 2a-d. The in vitro half-lives of 3a-d reached &tilde;30.4, 37.6, 29.5, and 33.9 h, respectively, surpassing that of liraglutide (&tilde;27.7 h). Because peptides are metabolized much faster in mice than in human [46], it is reasonable to envision that 3a-d will exhibit even longer hypoglycemic effects (>1 day) in human."	"Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice."
REF00110	PDC_00068	Fibrosarcoma	HT108 cells xenograft models in 6- to 8-week-old female balb/c nude or CB17-SCID mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor volume	1200 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	Fibrosarcoma	HT-1080 cell	0.4 hour (Mouse); 0.3 hour (Rat); 0.6 hour (Nonhuman primate)	.	20 day	0.167 mg/kg every week	.	"BT5528 is efficacious in the PC3 xenograft model but control BTCs with noncleavable linkers and non-cell penetrant toxins lack comparable efficacy. A, The nonbinding BTC, BCY8245, is less active than BT5528 in the PC3 model (group mean &plusmn; SEM, n = 5) at both 0.5 and 0.0167 mg/kg dosing level (*, P < 0.05; **, P < 0.01; two-way ANOVA with Sidak's multiple comparisons test). B, Replacement of the cell penetrant toxin (MMAE: BT5528) with the non-cell penetrant toxin (MMAF: BCY10188) reduces activity in the PC3 model at 3, 1, and 0.33 mg/kg (group mean &plusmn; SEM; n = 5; *, P < 0.05; **, P < 0.01; two-way ANOVA with Sidak's multiple comparisons test). C, noncleavable linker chemistry abolishes activity in the HT1080 model; BCY6063, 10 mg/kg twice a week (group mean &plusmn; SEM, n = 3)."	"Here we describe the development of BT5528, a bicyclic peptide (Bicycle) conjugated to the auristatin derivative maleimidocaproyl-monomethyl auristatin E to generate the Bicycle toxin conjugate BT5528. There are two potential mechanism of BT5528 bystander activity: extracellular linker cleavage and toxin penetration into neighboring cells, or receptor internalization and intracellular linker cleavage followed by release of cell penetrant toxin from lysed cells. The available data do not allow us to distinguish between these two mechanisms and it seems likely that BT5528 activity is mediated by toxin release following a combination of intracellular and extracellular linker cleavage."
REF00110	PDC_00068	Fibrosarcoma	HT108 cells xenograft models in 6- to 8-week-old female balb/c nude or CB17-SCID mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	50%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	0.4 hour (Mouse); 0.3 hour (Rat); 0.6 hour (Nonhuman primate)	.	20 day	0.167 mg/kg every week	.	"BT5528 is efficacious in the PC3 xenograft model but control BTCs with noncleavable linkers and non-cell penetrant toxins lack comparable efficacy. A, The nonbinding BTC, BCY8245, is less active than BT5528 in the PC3 model (group mean &plusmn; SEM, n = 5) at both 0.5 and 0.0167 mg/kg dosing level (*, P < 0.05; **, P < 0.01; two-way ANOVA with Sidak's multiple comparisons test). B, Replacement of the cell penetrant toxin (MMAE: BT5528) with the non-cell penetrant toxin (MMAF: BCY10188) reduces activity in the PC3 model at 3, 1, and 0.33 mg/kg (group mean &plusmn; SEM; n = 5; *, P < 0.05; **, P < 0.01; two-way ANOVA with Sidak's multiple comparisons test). C, noncleavable linker chemistry abolishes activity in the HT1080 model; BCY6063, 10 mg/kg twice a week (group mean &plusmn; SEM, n = 3)."	"Here we describe the development of BT5528, a bicyclic peptide (Bicycle) conjugated to the auristatin derivative maleimidocaproyl-monomethyl auristatin E to generate the Bicycle toxin conjugate BT5528. There are two potential mechanism of BT5528 bystander activity: extracellular linker cleavage and toxin penetration into neighboring cells, or receptor internalization and intracellular linker cleavage followed by release of cell penetrant toxin from lysed cells. The available data do not allow us to distinguish between these two mechanisms and it seems likely that BT5528 activity is mediated by toxin release following a combination of intracellular and extracellular linker cleavage."
REF00110	PDC_00068	Fibrosarcoma	HT108 cells xenograft models in 6- to 8-week-old female balb/c nude or CB17-SCID mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor volume	2200 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	Fibrosarcoma	HT-1080 cell	0.4 hour (Mouse); 0.3 hour (Rat); 0.6 hour (Nonhuman primate)	.	20 day	0.5 mg/kg every week	.	"BT5528 is efficacious in the PC3 xenograft model but control BTCs with noncleavable linkers and non-cell penetrant toxins lack comparable efficacy. A, The nonbinding BTC, BCY8245, is less active than BT5528 in the PC3 model (group mean &plusmn; SEM, n = 5) at both 0.5 and 0.0167 mg/kg dosing level (*, P < 0.05; **, P < 0.01; two-way ANOVA with Sidak's multiple comparisons test). B, Replacement of the cell penetrant toxin (MMAE: BT5528) with the non-cell penetrant toxin (MMAF: BCY10188) reduces activity in the PC3 model at 3, 1, and 0.33 mg/kg (group mean &plusmn; SEM; n = 5; *, P < 0.05; **, P < 0.01; two-way ANOVA with Sidak's multiple comparisons test). C, noncleavable linker chemistry abolishes activity in the HT1080 model; BCY6063, 10 mg/kg twice a week (group mean &plusmn; SEM, n = 3)."	"Here we describe the development of BT5528, a bicyclic peptide (Bicycle) conjugated to the auristatin derivative maleimidocaproyl-monomethyl auristatin E to generate the Bicycle toxin conjugate BT5528. There are two potential mechanism of BT5528 bystander activity: extracellular linker cleavage and toxin penetration into neighboring cells, or receptor internalization and intracellular linker cleavage followed by release of cell penetrant toxin from lysed cells. The available data do not allow us to distinguish between these two mechanisms and it seems likely that BT5528 activity is mediated by toxin release following a combination of intracellular and extracellular linker cleavage."
REF00110	PDC_00068	Fibrosarcoma	HT108 cells xenograft models in 6- to 8-week-old female balb/c nude or CB17-SCID mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	87%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	0.4 hour (Mouse); 0.3 hour (Rat); 0.6 hour (Nonhuman primate)	.	20 day	0.5 mg/kg every week	.	"BT5528 is efficacious in the PC3 xenograft model but control BTCs with noncleavable linkers and non-cell penetrant toxins lack comparable efficacy. A, The nonbinding BTC, BCY8245, is less active than BT5528 in the PC3 model (group mean &plusmn; SEM, n = 5) at both 0.5 and 0.0167 mg/kg dosing level (*, P < 0.05; **, P < 0.01; two-way ANOVA with Sidak's multiple comparisons test). B, Replacement of the cell penetrant toxin (MMAE: BT5528) with the non-cell penetrant toxin (MMAF: BCY10188) reduces activity in the PC3 model at 3, 1, and 0.33 mg/kg (group mean &plusmn; SEM; n = 5; *, P < 0.05; **, P < 0.01; two-way ANOVA with Sidak's multiple comparisons test). C, noncleavable linker chemistry abolishes activity in the HT1080 model; BCY6063, 10 mg/kg twice a week (group mean &plusmn; SEM, n = 3)."	"Here we describe the development of BT5528, a bicyclic peptide (Bicycle) conjugated to the auristatin derivative maleimidocaproyl-monomethyl auristatin E to generate the Bicycle toxin conjugate BT5528. There are two potential mechanism of BT5528 bystander activity: extracellular linker cleavage and toxin penetration into neighboring cells, or receptor internalization and intracellular linker cleavage followed by release of cell penetrant toxin from lysed cells. The available data do not allow us to distinguish between these two mechanisms and it seems likely that BT5528 activity is mediated by toxin release following a combination of intracellular and extracellular linker cleavage."
REF00112	PDC_00003	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	20.22 &micro;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	.	.	MTT colorimetric assay	"An MTT colorimetric assay was used to evaluate the in vitro cytotoxicity of materials on SMMC-7721 cells. Within the concentration range of 1.25-100 uM, DOX, DOX-SH, and PDC had a certain killing effect on liver cancer cells. The IC50 values of DOX, DOX-SH, and PDC were 17.62, 14.75, and 20.22 uM, respectively."	"Meanwhile, the thiol groups on Pep were used to covalently link it with a doxorubicin derivative (DOX-SH) and form PDC to kill tumors and inhibit tumor metastasis. Two doxorubicin molecules were linked to one Pep, and the drug loading was as high as 50.17%. The functional PDC molecule was synthesized from DOX-SH and 2,2-dipyridyl disulfide activated peptide (Pep-S-S-Py), and the molecular weight is 2565.98. CSNs were prepared for the effective codelivery of MMPI Pep and DOX to the tumor site. The MPL shell displayed a negative surface charge for prolonged blood circulation, and the PDC core was able to aggregate in the tumor matrix and adhere to the cell membrane. PDC aggregation could constantly release the MMPI peptide and DOX via low concentration and long-term glutathione-mediated reduction conditions in the tumor matrix. DOX can effectively enter the tumor cell and kill them. Meanwhile, MMPI peptide adherence to the cell membrane was able to selectively inhibit the activity of the MMP2 and achieve the effect of inhibiting tumor metastasis. Our study suggests that CSNs are of great potential for treating metastatic tumors."
REF00112	PDC_00003	Liver cancer	BALB/c male nude mice inoculated with high metastatic HCCLM3-LUC cells.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor volume	1500 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	Adult hepatocellular carcinoma	HCCLM3-Luc cell	.	.	24 day	6 mg/kg	.	"The antitumor activity of CSNs was assessed in BALB/c male nude mice inoculated with high metastatic HCCLM3-LUC cells. As can be seen from Figure 3A,B, DOX caused severe systemic toxicity and a significant weight loss (up to 24.38%) during treatment. In contrast, there was little change in body weight for PDC- and CSNs-treated mice. Tumor progression was greatly suppressed in the CSNs group, as observed by bioluminescence. Tumor tissue images collected on day 27 confirmed that nude mice treated with CSNs bore the smallest tumors."	"Meanwhile, the thiol groups on Pep were used to covalently link it with a doxorubicin derivative (DOX-SH) and form PDC to kill tumors and inhibit tumor metastasis. Two doxorubicin molecules were linked to one Pep, and the drug loading was as high as 50.17%. The functional PDC molecule was synthesized from DOX-SH and 2,2-dipyridyl disulfide activated peptide (Pep-S-S-Py), and the molecular weight is 2565.98. CSNs were prepared for the effective codelivery of MMPI Pep and DOX to the tumor site. The MPL shell displayed a negative surface charge for prolonged blood circulation, and the PDC core was able to aggregate in the tumor matrix and adhere to the cell membrane. PDC aggregation could constantly release the MMPI peptide and DOX via low concentration and long-term glutathione-mediated reduction conditions in the tumor matrix. DOX can effectively enter the tumor cell and kill them. Meanwhile, MMPI peptide adherence to the cell membrane was able to selectively inhibit the activity of the MMP2 and achieve the effect of inhibiting tumor metastasis. Our study suggests that CSNs are of great potential for treating metastatic tumors."
REF00112	PDC_00003	Liver cancer	BALB/c male nude mice inoculated with high metastatic HCCLM3-LUC cells.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	57.40%	%	.	.	.	.	Adult hepatocellular carcinoma	HCCLM3-Luc cell	.	.	24 day	6 mg/kg	.	"The antitumor activity of CSNs was assessed in BALB/c male nude mice inoculated with high metastatic HCCLM3-LUC cells. As can be seen from Figure 3A,B, DOX caused severe systemic toxicity and a significant weight loss (up to 24.38%) during treatment. In contrast, there was little change in body weight for PDC- and CSNs-treated mice. Tumor progression was greatly suppressed in the CSNs group, as observed by bioluminescence. Tumor tissue images collected on day 27 confirmed that nude mice treated with CSNs bore the smallest tumors."	"Meanwhile, the thiol groups on Pep were used to covalently link it with a doxorubicin derivative (DOX-SH) and form PDC to kill tumors and inhibit tumor metastasis. Two doxorubicin molecules were linked to one Pep, and the drug loading was as high as 50.17%. The functional PDC molecule was synthesized from DOX-SH and 2,2-dipyridyl disulfide activated peptide (Pep-S-S-Py), and the molecular weight is 2565.98. CSNs were prepared for the effective codelivery of MMPI Pep and DOX to the tumor site. The MPL shell displayed a negative surface charge for prolonged blood circulation, and the PDC core was able to aggregate in the tumor matrix and adhere to the cell membrane. PDC aggregation could constantly release the MMPI peptide and DOX via low concentration and long-term glutathione-mediated reduction conditions in the tumor matrix. DOX can effectively enter the tumor cell and kill them. Meanwhile, MMPI peptide adherence to the cell membrane was able to selectively inhibit the activity of the MMP2 and achieve the effect of inhibiting tumor metastasis. Our study suggests that CSNs are of great potential for treating metastatic tumors."
REF00112	PDC_00003	Liver cancer	BALB/c male nude mice inoculated with high metastatic HCCLM3-LUC cells.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Lung metastasis nodules inhibition rates	81.82%	%	.	.	.	.	Adult hepatocellular carcinoma	HCCLM3-Luc cell	.	.	5 week	6 mg/kg	H&E stain assay	"For the PDC- and CSN-treated groups, the number of lung metastasis nodules was decreased (inhibition rates of 81.82% and 93.18%, respectively), and smaller areas of tumor cells were observed in the H&E-stained images. Nude mice treated with DOX displayed 7.8 nodules, which was not significantly different from what was seen in the PBS group."	"Meanwhile, the thiol groups on Pep were used to covalently link it with a doxorubicin derivative (DOX-SH) and form PDC to kill tumors and inhibit tumor metastasis. Two doxorubicin molecules were linked to one Pep, and the drug loading was as high as 50.17%. The functional PDC molecule was synthesized from DOX-SH and 2,2-dipyridyl disulfide activated peptide (Pep-S-S-Py), and the molecular weight is 2565.98. CSNs were prepared for the effective codelivery of MMPI Pep and DOX to the tumor site. The MPL shell displayed a negative surface charge for prolonged blood circulation, and the PDC core was able to aggregate in the tumor matrix and adhere to the cell membrane. PDC aggregation could constantly release the MMPI peptide and DOX via low concentration and long-term glutathione-mediated reduction conditions in the tumor matrix. DOX can effectively enter the tumor cell and kill them. Meanwhile, MMPI peptide adherence to the cell membrane was able to selectively inhibit the activity of the MMP2 and achieve the effect of inhibiting tumor metastasis. Our study suggests that CSNs are of great potential for treating metastatic tumors."
REF00116	PDC_00045	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease stable rate	70%	%	.	.	.	10 patients with neuroendocrine tumour.	.	.	.	.	.	3.5&plusmn;0.3 GBq (94.7&plusmn;7.5 mCi)	68Ga-DOTATATE PET/CT assay	"During the follow-up period (24 wk), the best response was stable disease in 70% of subjects (7/10) and progressive disease in 20% (2/10)"	.
REF00117	PDC_00348	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	864 nM	nM	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	.	MTS cell proliferation assay	"All cell lines demonstrated sensitivity toward the DSA-PABA payload 5 in the nanomolar range. The cleaved peptide 6, and the benzyl protected control peptide 4, had no appreciable effect on cell proliferation (>100 uM), suggesting that any observed cytotoxic activity is due to the DSA warhead. Interestingly, PDC 7, without the cathepsin B cleavable sequence, also had no appreciable effect on cell proliferation (>100 uM), despite possessing the active DSA DNA alkylating moiety. Perhaps this PDC is either not being taken up into cells or not being broken down by proteases and peptidases in the cell. In both cases, the warhead may not be reaching the nucleus, the site of action of the duocarmycins. Cell lines that demonstrated appreciable levels of TF were sensitive to PDC 3. Interestingly, HCT116, which had relatively high TF expression and cathepsin B activity, demonstrated the greatest sensitivity to PDC 3, approaching similar potency to the payload 5. Excitingly, A549, H292, and 16HBE14o, which showed no detectable TF expression, appeared unaffected by PDC 3 up to 100 uM, suggesting that TF expression is required for the efficacy of PDC 3."	"The cancer phenotype is commonly associated with aberrant glycosylation patterns. One glycan that is directly linked to cancer is the Thomsen-Friedenreich antigen (TF or CD176). It is a disaccharide composed of a galactose &beta;1-3 N-acetylgalactosamine, O-linked to a glycoprotein through serine or threonine residues and commonly written as Gal&beta;1-3GalNAc--O-Ser/Thr. The TF is therapeutically attractive due to its cryptic nature in normal cells and exposure in embryonic and cancer cells. The expression of the TF has been demonstrated in 90% of primary human carcinomas, including in the lung, the breast, and the pancreas. Additionally, cancer initiating cells or cancer stem cells in the lung, liver, and colon express the TF. The peptide sequence HGRFILPWWYAFSPS (TF&alpha;-peptide) is known to bind tightly to the TF (Kd = 1.2 M) and has been demonstrated to inhibit processes directly involved in TF accessibility."
REF00117	PDC_00348	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	526 nM	nM	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	72 h	.	MTS cell proliferation assay	"All cell lines demonstrated sensitivity toward the DSA-PABA payload 5 in the nanomolar range. The cleaved peptide 6, and the benzyl protected control peptide 4, had no appreciable effect on cell proliferation (>100 uM), suggesting that any observed cytotoxic activity is due to the DSA warhead. Interestingly, PDC 7, without the cathepsin B cleavable sequence, also had no appreciable effect on cell proliferation (>100 uM), despite possessing the active DSA DNA alkylating moiety. Perhaps this PDC is either not being taken up into cells or not being broken down by proteases and peptidases in the cell. In both cases, the warhead may not be reaching the nucleus, the site of action of the duocarmycins. Cell lines that demonstrated appreciable levels of TF were sensitive to PDC 3. Interestingly, HCT116, which had relatively high TF expression and cathepsin B activity, demonstrated the greatest sensitivity to PDC 3, approaching similar potency to the payload 5. Excitingly, A549, H292, and 16HBE14o, which showed no detectable TF expression, appeared unaffected by PDC 3 up to 100 uM, suggesting that TF expression is required for the efficacy of PDC 3."	"As a payload for PDCs (and ADCs), analogues of the duocarmycins are attractive. Duocarmycin SA and yatakemycin rank among the most potent natural cytotoxins discovered. The cyclopropyl and prodrug seco forms are both naturally occurring and equipotent in most circumstances. Studies of the binding-driven bonding model of their interaction with DNA suggest that their utility will be enhanced when targeted to tumor cells. In fact, SYD985, an ADC that utilizes a peptide linker for a duocarmycin analogue to trastuzumab, has recently been progressed to phase III clinical trial."
REF00117	PDC_00348	Lung adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	.	72 h	.	MTS cell proliferation assay	"All cell lines demonstrated sensitivity toward the DSA-PABA payload 5 in the nanomolar range. The cleaved peptide 6, and the benzyl protected control peptide 4, had no appreciable effect on cell proliferation (>100 uM), suggesting that any observed cytotoxic activity is due to the DSA warhead. Interestingly, PDC 7, without the cathepsin B cleavable sequence, also had no appreciable effect on cell proliferation (>100 uM), despite possessing the active DSA DNA alkylating moiety. Perhaps this PDC is either not being taken up into cells or not being broken down by proteases and peptidases in the cell. In both cases, the warhead may not be reaching the nucleus, the site of action of the duocarmycins. Cell lines that demonstrated appreciable levels of TF were sensitive to PDC 3. Interestingly, HCT116, which had relatively high TF expression and cathepsin B activity, demonstrated the greatest sensitivity to PDC 3, approaching similar potency to the payload 5. Excitingly, A549, H292, and 16HBE14o, which showed no detectable TF expression, appeared unaffected by PDC 3 up to 100 uM, suggesting that TF expression is required for the efficacy of PDC 3."	"The cancer phenotype is commonly associated with aberrant glycosylation patterns. One glycan that is directly linked to cancer is the Thomsen-Friedenreich antigen (TF or CD176). It is a disaccharide composed of a galactose &beta;1-3 N-acetylgalactosamine, O-linked to a glycoprotein through serine or threonine residues and commonly written as Gal&beta;1-3GalNAc--O-Ser/Thr. The TF is therapeutically attractive due to its cryptic nature in normal cells and exposure in embryonic and cancer cells. The expression of the TF has been demonstrated in 90% of primary human carcinomas, including in the lung, the breast, and the pancreas. Additionally, cancer initiating cells or cancer stem cells in the lung, liver, and colon express the TF. The peptide sequence HGRFILPWWYAFSPS (TF-peptide) is known to bind tightly to the TF (Kd = 1.2 M) and has been demonstrated to inhibit processes directly involved in TF accessibility."
REF00117	PDC_00348	Lung mucoepidermoid carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Lung mucoepidermoid carcinoma	H292 cell	.	.	72 h	.	MTS cell proliferation assay	"All cell lines demonstrated sensitivity toward the DSA-PABA payload 5 in the nanomolar range. The cleaved peptide 6, and the benzyl protected control peptide 4, had no appreciable effect on cell proliferation (>100 uM), suggesting that any observed cytotoxic activity is due to the DSA warhead. Interestingly, PDC 7, without the cathepsin B cleavable sequence, also had no appreciable effect on cell proliferation (>100 uM), despite possessing the active DSA DNA alkylating moiety. Perhaps this PDC is either not being taken up into cells or not being broken down by proteases and peptidases in the cell. In both cases, the warhead may not be reaching the nucleus, the site of action of the duocarmycins. Cell lines that demonstrated appreciable levels of TF were sensitive to PDC 3. Interestingly, HCT116, which had relatively high TF expression and cathepsin B activity, demonstrated the greatest sensitivity to PDC 3, approaching similar potency to the payload 5. Excitingly, A549, H292, and 16HBE14o, which showed no detectable TF expression, appeared unaffected by PDC 3 up to 100 uM, suggesting that TF expression is required for the efficacy of PDC 3."	"As a payload for PDCs (and ADCs), analogues of the duocarmycins are attractive. Duocarmycin SA and yatakemycin rank among the most potent natural cytotoxins discovered. The cyclopropyl and prodrug seco forms are both naturally occurring and equipotent in most circumstances. Studies of the binding-driven bonding model of their interaction with DNA suggest that their utility will be enhanced when targeted to tumor cells. In fact, SYD985, an ADC that utilizes a peptide linker for a duocarmycin analogue to trastuzumab, has recently been progressed to phase III clinical trial."
REF00117	PDC_00348	Colon adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	402 nM	nM	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	72 h	.	MTS cell proliferation assay	"All cell lines demonstrated sensitivity toward the DSA-PABA payload 5 in the nanomolar range. The cleaved peptide 6, and the benzyl protected control peptide 4, had no appreciable effect on cell proliferation (>100 uM), suggesting that any observed cytotoxic activity is due to the DSA warhead. Interestingly, PDC 7, without the cathepsin B cleavable sequence, also had no appreciable effect on cell proliferation (>100 uM), despite possessing the active DSA DNA alkylating moiety. Perhaps this PDC is either not being taken up into cells or not being broken down by proteases and peptidases in the cell. In both cases, the warhead may not be reaching the nucleus, the site of action of the duocarmycins. Cell lines that demonstrated appreciable levels of TF were sensitive to PDC 3. Interestingly, HCT116, which had relatively high TF expression and cathepsin B activity, demonstrated the greatest sensitivity to PDC 3, approaching similar potency to the payload 5. Excitingly, A549, H292, and 16HBE14o, which showed no detectable TF expression, appeared unaffected by PDC 3 up to 100 uM, suggesting that TF expression is required for the efficacy of PDC 3."	"The cancer phenotype is commonly associated with aberrant glycosylation patterns. One glycan that is directly linked to cancer is the Thomsen-Friedenreich antigen (TF or CD176). It is a disaccharide composed of a galactose &beta;1-3 N-acetylgalactosamine, O-linked to a glycoprotein through serine or threonine residues and commonly written as Gal&beta;1-3GalNAc--O-Ser/Thr. The TF is therapeutically attractive due to its cryptic nature in normal cells and exposure in embryonic and cancer cells. The expression of the TF has been demonstrated in 90% of primary human carcinomas, including in the lung, the breast, and the pancreas. Additionally, cancer initiating cells or cancer stem cells in the lung, liver, and colon express the TF. The peptide sequence HGRFILPWWYAFSPS (TF-peptide) is known to bind tightly to the TF (Kd = 1.2 M) and has been demonstrated to inhibit processes directly involved in TF accessibility."
REF00117	PDC_00348	Fibrosarcoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8266 nM	nM	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	72 h	.	MTS cell proliferation assay	"All cell lines demonstrated sensitivity toward the DSA-PABA payload 5 in the nanomolar range. The cleaved peptide 6, and the benzyl protected control peptide 4, had no appreciable effect on cell proliferation (>100 uM), suggesting that any observed cytotoxic activity is due to the DSA warhead. Interestingly, PDC 7, without the cathepsin B cleavable sequence, also had no appreciable effect on cell proliferation (>100 uM), despite possessing the active DSA DNA alkylating moiety. Perhaps this PDC is either not being taken up into cells or not being broken down by proteases and peptidases in the cell. In both cases, the warhead may not be reaching the nucleus, the site of action of the duocarmycins. Cell lines that demonstrated appreciable levels of TF were sensitive to PDC 3. Interestingly, HCT116, which had relatively high TF expression and cathepsin B activity, demonstrated the greatest sensitivity to PDC 3, approaching similar potency to the payload 5. Excitingly, A549, H292, and 16HBE14o, which showed no detectable TF expression, appeared unaffected by PDC 3 up to 100 uM, suggesting that TF expression is required for the efficacy of PDC 3."	"As a payload for PDCs (and ADCs), analogues of the duocarmycins are attractive. Duocarmycin SA and yatakemycin rank among the most potent natural cytotoxins discovered. The cyclopropyl and prodrug seco forms are both naturally occurring and equipotent in most circumstances. Studies of the binding-driven bonding model of their interaction with DNA suggest that their utility will be enhanced when targeted to tumor cells. In fact, SYD985, an ADC that utilizes a peptide linker for a duocarmycin analogue to trastuzumab, has recently been progressed to phase III clinical trial."
REF00117	PDC_00348	Acute myeloid leukemia	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1831 nM	nM	.	.	.	.	Acute myeloid leukemia	HL-60 cell	.	.	72 h	.	MTS cell proliferation assay	"All cell lines demonstrated sensitivity toward the DSA-PABA payload 5 in the nanomolar range. The cleaved peptide 6, and the benzyl protected control peptide 4, had no appreciable effect on cell proliferation (>100 uM), suggesting that any observed cytotoxic activity is due to the DSA warhead. Interestingly, PDC 7, without the cathepsin B cleavable sequence, also had no appreciable effect on cell proliferation (>100 uM), despite possessing the active DSA DNA alkylating moiety. Perhaps this PDC is either not being taken up into cells or not being broken down by proteases and peptidases in the cell. In both cases, the warhead may not be reaching the nucleus, the site of action of the duocarmycins. Cell lines that demonstrated appreciable levels of TF were sensitive to PDC 3. Interestingly, HCT116, which had relatively high TF expression and cathepsin B activity, demonstrated the greatest sensitivity to PDC 3, approaching similar potency to the payload 5. Excitingly, A549, H292, and 16HBE14o, which showed no detectable TF expression, appeared unaffected by PDC 3 up to 100 uM, suggesting that TF expression is required for the efficacy of PDC 3."	"The cancer phenotype is commonly associated with aberrant glycosylation patterns. One glycan that is directly linked to cancer is the Thomsen-Friedenreich antigen (TF or CD176). It is a disaccharide composed of a galactose &beta;1-3 N-acetylgalactosamine, O-linked to a glycoprotein through serine or threonine residues and commonly written as Gal&beta;1-3GalNAc--O-Ser/Thr. The TF is therapeutically attractive due to its cryptic nature in normal cells and exposure in embryonic and cancer cells. The expression of the TF has been demonstrated in 90% of primary human carcinomas, including in the lung, the breast, and the pancreas. Additionally, cancer initiating cells or cancer stem cells in the lung, liver, and colon express the TF. The peptide sequence HGRFILPWWYAFSPS (TF-peptide) is known to bind tightly to the TF (Kd = 1.2 M) and has been demonstrated to inhibit processes directly involved in TF accessibility."
REF00117	PDC_00348	Normal	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Normal	16HBE14o- cell	.	.	72 h	.	MTS cell proliferation assay	"All cell lines demonstrated sensitivity toward the DSA-PABA payload 5 in the nanomolar range. The cleaved peptide 6, and the benzyl protected control peptide 4, had no appreciable effect on cell proliferation (>100 uM), suggesting that any observed cytotoxic activity is due to the DSA warhead. Interestingly, PDC 7, without the cathepsin B cleavable sequence, also had no appreciable effect on cell proliferation (>100 uM), despite possessing the active DSA DNA alkylating moiety. Perhaps this PDC is either not being taken up into cells or not being broken down by proteases and peptidases in the cell. In both cases, the warhead may not be reaching the nucleus, the site of action of the duocarmycins. Cell lines that demonstrated appreciable levels of TF were sensitive to PDC 3. Interestingly, HCT116, which had relatively high TF expression and cathepsin B activity, demonstrated the greatest sensitivity to PDC 3, approaching similar potency to the payload 5. Excitingly, A549, H292, and 16HBE14o, which showed no detectable TF expression, appeared unaffected by PDC 3 up to 100 uM, suggesting that TF expression is required for the efficacy of PDC 3."	"As a payload for PDCs (and ADCs), analogues of the duocarmycins are attractive. Duocarmycin SA and yatakemycin rank among the most potent natural cytotoxins discovered. The cyclopropyl and prodrug seco forms are both naturally occurring and equipotent in most circumstances. Studies of the binding-driven bonding model of their interaction with DNA suggest that their utility will be enhanced when targeted to tumor cells. In fact, SYD985, an ADC that utilizes a peptide linker for a duocarmycin analogue to trastuzumab, has recently been progressed to phase III clinical trial."
REF00118	PDC_00123	Colon adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.2 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	48 h	.	xCELLigence SP system assay	"The polymers influenced the cellular uptake of the conjugates in a different manner, but in both groups (GE11 and D4 containing conjugates), one of the compounds was outstanding. The HT-29 cells could uptake Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG to the highest extent. The G5 spacer increased the uptake of the D4-HbPG derivative, presumably because the increased distance between the globular HbPG and the very short peptide sequence provides a better receptor binding. In sharp contrast, the G5 spacer decreases the uptake of the conjugates in all other cases. The most significant difference was observed in the case of GE11-PEG, where the G5 spacer completely demolished the internalization. Probably, here the G5 spacer provides more flexibility for the linear PEG chain resulting in decreased receptor binding. There was one outstanding conjugate from each group (Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG) in the cytotoxicity measurements that correlated well with the results of the internalization studies. These conjugates were found to be the most potent ones in the viability measurement and were proved to be taken up by HT-29 cells the most effectively. Depending on the type of polymer, the incorporation of the G5 spacer had an opposite effect on the cytotoxic activity of the conjugates. In the presence of the G5 spacer, the antitumour activity of the PEGylated conjugates decreased, while the cytotoxicity of the HbPG-containing conjugates increased, especially in the case of those with the D4 targeting peptide. We observed that some of the conjugates (Dau[double bond, length as m-dash]Aoa-GFLG-D4-HbPG and Dau[double bond, length as m-dash]Aoa-GFLG-GE11-G5-PEG) could not cause complete cell death, i.e., &tilde;0% viability value - characteristic for cell-free culturing medium - was not achieved even at the highest concentration, since their dose-response curves reached a plateau in a lower concentration range. In our opinion, this can be explained by the different characteristics of the highly hydrophobic peptide chain and the highly hydrophilic polymer segment. Due to this amphiphilic character, self-aggregation of the conjugates may occur, which then may block the accessibility of the targeting peptide for receptor binding, thereby decreasing the efficiency of the conjugate as well. This assumption is also confirmed by the turbidity results, since the observed low turbidity values may be caused by the possible formation of nanosized aggregates."	"As observed, the cathepsin B labile spacer (GFLG), which was incorporated between the targeting peptide and the daunomycin to ensure the efficient release of the active metabolite, highly increases the hydrophobicity of the conjugates. As demonstrated, the solubility problem of these conjugates can be solved by hydrophilic polymer coupling, not only by using the well-known PEG but also by using the amino-monofunctional HbPG. To the best of our knowledge, 1:1 covalent peptide-polymer conjugates with well-defined monofunctional HbPG have been reported here for the first time. The results of the in vitro cell viability and cellular uptake measurements on HT-29 human colon adenocarcinoma cells prove that the HbPG and the PEG highly influenced the biological activity of the drug-peptide-polymer conjugates. In both peptide conjugate series, one GE11 and one D4 targeting peptide-based conjugate were found with outstanding cellular uptake and cytotoxicity values, namely Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG. According to our results, the PEG is suitable for longer targeting peptides (e.g. GE11), but the G5 spacer is not suitable irrespective of the length of the peptide because it may decrease the biological effect by increasing the flexibility of the polymer and shading of the targeting moiety. In contrast, the use of the hydrophilic hyperbranched polyglycerol (HbPG) is advantageous for short targeting peptides (e.g. D4) but only with a G5 spacer, which provides accessibility of the peptide for receptor binding and cellular uptake resulting in outstanding cytotoxicity."
REF00118	PDC_00121	Colon adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.1 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	48 h	.	xCELLigence SP system assay	"The polymers influenced the cellular uptake of the conjugates in a different manner, but in both groups (GE11 and D4 containing conjugates), one of the compounds was outstanding. The HT-29 cells could uptake Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG to the highest extent. The G5 spacer increased the uptake of the D4-HbPG derivative, presumably because the increased distance between the globular HbPG and the very short peptide sequence provides a better receptor binding. In sharp contrast, the G5 spacer decreases the uptake of the conjugates in all other cases. The most significant difference was observed in the case of GE11-PEG, where the G5 spacer completely demolished the internalization. Probably, here the G5 spacer provides more flexibility for the linear PEG chain resulting in decreased receptor binding. There was one outstanding conjugate from each group (Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG) in the cytotoxicity measurements that correlated well with the results of the internalization studies. These conjugates were found to be the most potent ones in the viability measurement and were proved to be taken up by HT-29 cells the most effectively. Depending on the type of polymer, the incorporation of the G5 spacer had an opposite effect on the cytotoxic activity of the conjugates. In the presence of the G5 spacer, the antitumour activity of the PEGylated conjugates decreased, while the cytotoxicity of the HbPG-containing conjugates increased, especially in the case of those with the D4 targeting peptide. We observed that some of the conjugates (Dau[double bond, length as m-dash]Aoa-GFLG-D4-HbPG and Dau[double bond, length as m-dash]Aoa-GFLG-GE11-G5-PEG) could not cause complete cell death, i.e., &tilde;0% viability value - characteristic for cell-free culturing medium - was not achieved even at the highest concentration, since their dose-response curves reached a plateau in a lower concentration range. In our opinion, this can be explained by the different characteristics of the highly hydrophobic peptide chain and the highly hydrophilic polymer segment. Due to this amphiphilic character, self-aggregation of the conjugates may occur, which then may block the accessibility of the targeting peptide for receptor binding, thereby decreasing the efficiency of the conjugate as well. This assumption is also confirmed by the turbidity results, since the observed low turbidity values may be caused by the possible formation of nanosized aggregates."	"As observed, the cathepsin B labile spacer (GFLG), which was incorporated between the targeting peptide and the daunomycin to ensure the efficient release of the active metabolite, highly increases the hydrophobicity of the conjugates. As demonstrated, the solubility problem of these conjugates can be solved by hydrophilic polymer coupling, not only by using the well-known PEG but also by using the amino-monofunctional HbPG. To the best of our knowledge, 1:1 covalent peptide-polymer conjugates with well-defined monofunctional HbPG have been reported here for the first time. The results of the in vitro cell viability and cellular uptake measurements on HT-29 human colon adenocarcinoma cells prove that the HbPG and the PEG highly influenced the biological activity of the drug-peptide-polymer conjugates. In both peptide conjugate series, one GE11 and one D4 targeting peptide-based conjugate were found with outstanding cellular uptake and cytotoxicity values, namely Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG. According to our results, the PEG is suitable for longer targeting peptides (e.g. GE11), but the G5 spacer is not suitable irrespective of the length of the peptide because it may decrease the biological effect by increasing the flexibility of the polymer and shading of the targeting moiety. In contrast, the use of the hydrophilic hyperbranched polyglycerol (HbPG) is advantageous for short targeting peptides (e.g. D4) but only with a G5 spacer, which provides accessibility of the peptide for receptor binding and cellular uptake resulting in outstanding cytotoxicity."
REF00118	PDC_00122	Colon adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.3 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	48 h	.	xCELLigence SP system assay	"The polymers influenced the cellular uptake of the conjugates in a different manner, but in both groups (GE11 and D4 containing conjugates), one of the compounds was outstanding. The HT-29 cells could uptake Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG to the highest extent. The G5 spacer increased the uptake of the D4-HbPG derivative, presumably because the increased distance between the globular HbPG and the very short peptide sequence provides a better receptor binding. In sharp contrast, the G5 spacer decreases the uptake of the conjugates in all other cases. The most significant difference was observed in the case of GE11-PEG, where the G5 spacer completely demolished the internalization. Probably, here the G5 spacer provides more flexibility for the linear PEG chain resulting in decreased receptor binding. There was one outstanding conjugate from each group (Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG) in the cytotoxicity measurements that correlated well with the results of the internalization studies. These conjugates were found to be the most potent ones in the viability measurement and were proved to be taken up by HT-29 cells the most effectively. Depending on the type of polymer, the incorporation of the G5 spacer had an opposite effect on the cytotoxic activity of the conjugates. In the presence of the G5 spacer, the antitumour activity of the PEGylated conjugates decreased, while the cytotoxicity of the HbPG-containing conjugates increased, especially in the case of those with the D4 targeting peptide. We observed that some of the conjugates (Dau[double bond, length as m-dash]Aoa-GFLG-D4-HbPG and Dau[double bond, length as m-dash]Aoa-GFLG-GE11-G5-PEG) could not cause complete cell death, i.e., &tilde;0% viability value - characteristic for cell-free culturing medium - was not achieved even at the highest concentration, since their dose-response curves reached a plateau in a lower concentration range. In our opinion, this can be explained by the different characteristics of the highly hydrophobic peptide chain and the highly hydrophilic polymer segment. Due to this amphiphilic character, self-aggregation of the conjugates may occur, which then may block the accessibility of the targeting peptide for receptor binding, thereby decreasing the efficiency of the conjugate as well. This assumption is also confirmed by the turbidity results, since the observed low turbidity values may be caused by the possible formation of nanosized aggregates."	"As observed, the cathepsin B labile spacer (GFLG), which was incorporated between the targeting peptide and the daunomycin to ensure the efficient release of the active metabolite, highly increases the hydrophobicity of the conjugates. As demonstrated, the solubility problem of these conjugates can be solved by hydrophilic polymer coupling, not only by using the well-known PEG but also by using the amino-monofunctional HbPG. To the best of our knowledge, 1:1 covalent peptide-polymer conjugates with well-defined monofunctional HbPG have been reported here for the first time. The results of the in vitro cell viability and cellular uptake measurements on HT-29 human colon adenocarcinoma cells prove that the HbPG and the PEG highly influenced the biological activity of the drug-peptide-polymer conjugates. In both peptide conjugate series, one GE11 and one D4 targeting peptide-based conjugate were found with outstanding cellular uptake and cytotoxicity values, namely Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG. According to our results, the PEG is suitable for longer targeting peptides (e.g. GE11), but the G5 spacer is not suitable irrespective of the length of the peptide because it may decrease the biological effect by increasing the flexibility of the polymer and shading of the targeting moiety. In contrast, the use of the hydrophilic hyperbranched polyglycerol (HbPG) is advantageous for short targeting peptides (e.g. D4) but only with a G5 spacer, which provides accessibility of the peptide for receptor binding and cellular uptake resulting in outstanding cytotoxicity."
REF00118	PDC_00120	Colon adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	48 h	.	xCELLigence SP system assay	"The polymers influenced the cellular uptake of the conjugates in a different manner, but in both groups (GE11 and D4 containing conjugates), one of the compounds was outstanding. The HT-29 cells could uptake Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG to the highest extent. The G5 spacer increased the uptake of the D4-HbPG derivative, presumably because the increased distance between the globular HbPG and the very short peptide sequence provides a better receptor binding. In sharp contrast, the G5 spacer decreases the uptake of the conjugates in all other cases. The most significant difference was observed in the case of GE11-PEG, where the G5 spacer completely demolished the internalization. Probably, here the G5 spacer provides more flexibility for the linear PEG chain resulting in decreased receptor binding. There was one outstanding conjugate from each group (Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG) in the cytotoxicity measurements that correlated well with the results of the internalization studies. These conjugates were found to be the most potent ones in the viability measurement and were proved to be taken up by HT-29 cells the most effectively. Depending on the type of polymer, the incorporation of the G5 spacer had an opposite effect on the cytotoxic activity of the conjugates. In the presence of the G5 spacer, the antitumour activity of the PEGylated conjugates decreased, while the cytotoxicity of the HbPG-containing conjugates increased, especially in the case of those with the D4 targeting peptide. We observed that some of the conjugates (Dau[double bond, length as m-dash]Aoa-GFLG-D4-HbPG and Dau[double bond, length as m-dash]Aoa-GFLG-GE11-G5-PEG) could not cause complete cell death, i.e., &tilde;0% viability value - characteristic for cell-free culturing medium - was not achieved even at the highest concentration, since their dose-response curves reached a plateau in a lower concentration range. In our opinion, this can be explained by the different characteristics of the highly hydrophobic peptide chain and the highly hydrophilic polymer segment. Due to this amphiphilic character, self-aggregation of the conjugates may occur, which then may block the accessibility of the targeting peptide for receptor binding, thereby decreasing the efficiency of the conjugate as well. This assumption is also confirmed by the turbidity results, since the observed low turbidity values may be caused by the possible formation of nanosized aggregates."	"As observed, the cathepsin B labile spacer (GFLG), which was incorporated between the targeting peptide and the daunomycin to ensure the efficient release of the active metabolite, highly increases the hydrophobicity of the conjugates. As demonstrated, the solubility problem of these conjugates can be solved by hydrophilic polymer coupling, not only by using the well-known PEG but also by using the amino-monofunctional HbPG. To the best of our knowledge, 1:1 covalent peptide-polymer conjugates with well-defined monofunctional HbPG have been reported here for the first time. The results of the in vitro cell viability and cellular uptake measurements on HT-29 human colon adenocarcinoma cells prove that the HbPG and the PEG highly influenced the biological activity of the drug-peptide-polymer conjugates. In both peptide conjugate series, one GE11 and one D4 targeting peptide-based conjugate were found with outstanding cellular uptake and cytotoxicity values, namely Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG. According to our results, the PEG is suitable for longer targeting peptides (e.g. GE11), but the G5 spacer is not suitable irrespective of the length of the peptide because it may decrease the biological effect by increasing the flexibility of the polymer and shading of the targeting moiety. In contrast, the use of the hydrophilic hyperbranched polyglycerol (HbPG) is advantageous for short targeting peptides (e.g. D4) but only with a G5 spacer, which provides accessibility of the peptide for receptor binding and cellular uptake resulting in outstanding cytotoxicity."
REF00118	PDC_00119	Colon adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.1 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	48 h	.	xCELLigence SP system assay	"The polymers influenced the cellular uptake of the conjugates in a different manner, but in both groups (GE11 and D4 containing conjugates), one of the compounds was outstanding. The HT-29 cells could uptake Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG to the highest extent. The G5 spacer increased the uptake of the D4-HbPG derivative, presumably because the increased distance between the globular HbPG and the very short peptide sequence provides a better receptor binding. In sharp contrast, the G5 spacer decreases the uptake of the conjugates in all other cases. The most significant difference was observed in the case of GE11-PEG, where the G5 spacer completely demolished the internalization. Probably, here the G5 spacer provides more flexibility for the linear PEG chain resulting in decreased receptor binding. There was one outstanding conjugate from each group (Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG) in the cytotoxicity measurements that correlated well with the results of the internalization studies. These conjugates were found to be the most potent ones in the viability measurement and were proved to be taken up by HT-29 cells the most effectively. Depending on the type of polymer, the incorporation of the G5 spacer had an opposite effect on the cytotoxic activity of the conjugates. In the presence of the G5 spacer, the antitumour activity of the PEGylated conjugates decreased, while the cytotoxicity of the HbPG-containing conjugates increased, especially in the case of those with the D4 targeting peptide. We observed that some of the conjugates (Dau[double bond, length as m-dash]Aoa-GFLG-D4-HbPG and Dau[double bond, length as m-dash]Aoa-GFLG-GE11-G5-PEG) could not cause complete cell death, i.e., &tilde;0% viability value - characteristic for cell-free culturing medium - was not achieved even at the highest concentration, since their dose-response curves reached a plateau in a lower concentration range. In our opinion, this can be explained by the different characteristics of the highly hydrophobic peptide chain and the highly hydrophilic polymer segment. Due to this amphiphilic character, self-aggregation of the conjugates may occur, which then may block the accessibility of the targeting peptide for receptor binding, thereby decreasing the efficiency of the conjugate as well. This assumption is also confirmed by the turbidity results, since the observed low turbidity values may be caused by the possible formation of nanosized aggregates."	"As observed, the cathepsin B labile spacer (GFLG), which was incorporated between the targeting peptide and the daunomycin to ensure the efficient release of the active metabolite, highly increases the hydrophobicity of the conjugates. As demonstrated, the solubility problem of these conjugates can be solved by hydrophilic polymer coupling, not only by using the well-known PEG but also by using the amino-monofunctional HbPG. To the best of our knowledge, 1:1 covalent peptide-polymer conjugates with well-defined monofunctional HbPG have been reported here for the first time. The results of the in vitro cell viability and cellular uptake measurements on HT-29 human colon adenocarcinoma cells prove that the HbPG and the PEG highly influenced the biological activity of the drug-peptide-polymer conjugates. In both peptide conjugate series, one GE11 and one D4 targeting peptide-based conjugate were found with outstanding cellular uptake and cytotoxicity values, namely Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG. According to our results, the PEG is suitable for longer targeting peptides (e.g. GE11), but the G5 spacer is not suitable irrespective of the length of the peptide because it may decrease the biological effect by increasing the flexibility of the polymer and shading of the targeting moiety. In contrast, the use of the hydrophilic hyperbranched polyglycerol (HbPG) is advantageous for short targeting peptides (e.g. D4) but only with a G5 spacer, which provides accessibility of the peptide for receptor binding and cellular uptake resulting in outstanding cytotoxicity."
REF00118	PDC_00117	Colon adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	13.5 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	48 h	.	xCELLigence SP system assay	"The polymers influenced the cellular uptake of the conjugates in a different manner, but in both groups (GE11 and D4 containing conjugates), one of the compounds was outstanding. The HT-29 cells could uptake Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG to the highest extent. The G5 spacer increased the uptake of the D4-HbPG derivative, presumably because the increased distance between the globular HbPG and the very short peptide sequence provides a better receptor binding. In sharp contrast, the G5 spacer decreases the uptake of the conjugates in all other cases. The most significant difference was observed in the case of GE11-PEG, where the G5 spacer completely demolished the internalization. Probably, here the G5 spacer provides more flexibility for the linear PEG chain resulting in decreased receptor binding. There was one outstanding conjugate from each group (Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG) in the cytotoxicity measurements that correlated well with the results of the internalization studies. These conjugates were found to be the most potent ones in the viability measurement and were proved to be taken up by HT-29 cells the most effectively. Depending on the type of polymer, the incorporation of the G5 spacer had an opposite effect on the cytotoxic activity of the conjugates. In the presence of the G5 spacer, the antitumour activity of the PEGylated conjugates decreased, while the cytotoxicity of the HbPG-containing conjugates increased, especially in the case of those with the D4 targeting peptide. We observed that some of the conjugates (Dau[double bond, length as m-dash]Aoa-GFLG-D4-HbPG and Dau[double bond, length as m-dash]Aoa-GFLG-GE11-G5-PEG) could not cause complete cell death, i.e., &tilde;0% viability value - characteristic for cell-free culturing medium - was not achieved even at the highest concentration, since their dose-response curves reached a plateau in a lower concentration range. In our opinion, this can be explained by the different characteristics of the highly hydrophobic peptide chain and the highly hydrophilic polymer segment. Due to this amphiphilic character, self-aggregation of the conjugates may occur, which then may block the accessibility of the targeting peptide for receptor binding, thereby decreasing the efficiency of the conjugate as well. This assumption is also confirmed by the turbidity results, since the observed low turbidity values may be caused by the possible formation of nanosized aggregates."	"As observed, the cathepsin B labile spacer (GFLG), which was incorporated between the targeting peptide and the daunomycin to ensure the efficient release of the active metabolite, highly increases the hydrophobicity of the conjugates. As demonstrated, the solubility problem of these conjugates can be solved by hydrophilic polymer coupling, not only by using the well-known PEG but also by using the amino-monofunctional HbPG. To the best of our knowledge, 1:1 covalent peptide-polymer conjugates with well-defined monofunctional HbPG have been reported here for the first time. The results of the in vitro cell viability and cellular uptake measurements on HT-29 human colon adenocarcinoma cells prove that the HbPG and the PEG highly influenced the biological activity of the drug-peptide-polymer conjugates. In both peptide conjugate series, one GE11 and one D4 targeting peptide-based conjugate were found with outstanding cellular uptake and cytotoxicity values, namely Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG. According to our results, the PEG is suitable for longer targeting peptides (e.g. GE11), but the G5 spacer is not suitable irrespective of the length of the peptide because it may decrease the biological effect by increasing the flexibility of the polymer and shading of the targeting moiety. In contrast, the use of the hydrophilic hyperbranched polyglycerol (HbPG) is advantageous for short targeting peptides (e.g. D4) but only with a G5 spacer, which provides accessibility of the peptide for receptor binding and cellular uptake resulting in outstanding cytotoxicity."
REF00118	PDC_00118	Colon adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	450 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	48 h	.	xCELLigence SP system assay	"The polymers influenced the cellular uptake of the conjugates in a different manner, but in both groups (GE11 and D4 containing conjugates), one of the compounds was outstanding. The HT-29 cells could uptake Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG to the highest extent. The G5 spacer increased the uptake of the D4-HbPG derivative, presumably because the increased distance between the globular HbPG and the very short peptide sequence provides a better receptor binding. In sharp contrast, the G5 spacer decreases the uptake of the conjugates in all other cases. The most significant difference was observed in the case of GE11-PEG, where the G5 spacer completely demolished the internalization. Probably, here the G5 spacer provides more flexibility for the linear PEG chain resulting in decreased receptor binding. There was one outstanding conjugate from each group (Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG) in the cytotoxicity measurements that correlated well with the results of the internalization studies. These conjugates were found to be the most potent ones in the viability measurement and were proved to be taken up by HT-29 cells the most effectively. Depending on the type of polymer, the incorporation of the G5 spacer had an opposite effect on the cytotoxic activity of the conjugates. In the presence of the G5 spacer, the antitumour activity of the PEGylated conjugates decreased, while the cytotoxicity of the HbPG-containing conjugates increased, especially in the case of those with the D4 targeting peptide. We observed that some of the conjugates (Dau[double bond, length as m-dash]Aoa-GFLG-D4-HbPG and Dau[double bond, length as m-dash]Aoa-GFLG-GE11-G5-PEG) could not cause complete cell death, i.e., &tilde;0% viability value - characteristic for cell-free culturing medium - was not achieved even at the highest concentration, since their dose-response curves reached a plateau in a lower concentration range. In our opinion, this can be explained by the different characteristics of the highly hydrophobic peptide chain and the highly hydrophilic polymer segment. Due to this amphiphilic character, self-aggregation of the conjugates may occur, which then may block the accessibility of the targeting peptide for receptor binding, thereby decreasing the efficiency of the conjugate as well. This assumption is also confirmed by the turbidity results, since the observed low turbidity values may be caused by the possible formation of nanosized aggregates."	"As observed, the cathepsin B labile spacer (GFLG), which was incorporated between the targeting peptide and the daunomycin to ensure the efficient release of the active metabolite, highly increases the hydrophobicity of the conjugates. As demonstrated, the solubility problem of these conjugates can be solved by hydrophilic polymer coupling, not only by using the well-known PEG but also by using the amino-monofunctional HbPG. To the best of our knowledge, 1:1 covalent peptide-polymer conjugates with well-defined monofunctional HbPG have been reported here for the first time. The results of the in vitro cell viability and cellular uptake measurements on HT-29 human colon adenocarcinoma cells prove that the HbPG and the PEG highly influenced the biological activity of the drug-peptide-polymer conjugates. In both peptide conjugate series, one GE11 and one D4 targeting peptide-based conjugate were found with outstanding cellular uptake and cytotoxicity values, namely Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG. According to our results, the PEG is suitable for longer targeting peptides (e.g. GE11), but the G5 spacer is not suitable irrespective of the length of the peptide because it may decrease the biological effect by increasing the flexibility of the polymer and shading of the targeting moiety. In contrast, the use of the hydrophilic hyperbranched polyglycerol (HbPG) is advantageous for short targeting peptides (e.g. D4) but only with a G5 spacer, which provides accessibility of the peptide for receptor binding and cellular uptake resulting in outstanding cytotoxicity."
REF00118	PDC_00116	Colon adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.8 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	48 h	.	xCELLigence SP system assay	"The polymers influenced the cellular uptake of the conjugates in a different manner, but in both groups (GE11 and D4 containing conjugates), one of the compounds was outstanding. The HT-29 cells could uptake Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG to the highest extent. The G5 spacer increased the uptake of the D4-HbPG derivative, presumably because the increased distance between the globular HbPG and the very short peptide sequence provides a better receptor binding. In sharp contrast, the G5 spacer decreases the uptake of the conjugates in all other cases. The most significant difference was observed in the case of GE11-PEG, where the G5 spacer completely demolished the internalization. Probably, here the G5 spacer provides more flexibility for the linear PEG chain resulting in decreased receptor binding. There was one outstanding conjugate from each group (Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG) in the cytotoxicity measurements that correlated well with the results of the internalization studies. These conjugates were found to be the most potent ones in the viability measurement and were proved to be taken up by HT-29 cells the most effectively. Depending on the type of polymer, the incorporation of the G5 spacer had an opposite effect on the cytotoxic activity of the conjugates. In the presence of the G5 spacer, the antitumour activity of the PEGylated conjugates decreased, while the cytotoxicity of the HbPG-containing conjugates increased, especially in the case of those with the D4 targeting peptide. We observed that some of the conjugates (Dau[double bond, length as m-dash]Aoa-GFLG-D4-HbPG and Dau[double bond, length as m-dash]Aoa-GFLG-GE11-G5-PEG) could not cause complete cell death, i.e., &tilde;0% viability value - characteristic for cell-free culturing medium - was not achieved even at the highest concentration, since their dose-response curves reached a plateau in a lower concentration range. In our opinion, this can be explained by the different characteristics of the highly hydrophobic peptide chain and the highly hydrophilic polymer segment. Due to this amphiphilic character, self-aggregation of the conjugates may occur, which then may block the accessibility of the targeting peptide for receptor binding, thereby decreasing the efficiency of the conjugate as well. This assumption is also confirmed by the turbidity results, since the observed low turbidity values may be caused by the possible formation of nanosized aggregates."	"As observed, the cathepsin B labile spacer (GFLG), which was incorporated between the targeting peptide and the daunomycin to ensure the efficient release of the active metabolite, highly increases the hydrophobicity of the conjugates. As demonstrated, the solubility problem of these conjugates can be solved by hydrophilic polymer coupling, not only by using the well-known PEG but also by using the amino-monofunctional HbPG. To the best of our knowledge, 1:1 covalent peptide-polymer conjugates with well-defined monofunctional HbPG have been reported here for the first time. The results of the in vitro cell viability and cellular uptake measurements on HT-29 human colon adenocarcinoma cells prove that the HbPG and the PEG highly influenced the biological activity of the drug-peptide-polymer conjugates. In both peptide conjugate series, one GE11 and one D4 targeting peptide-based conjugate were found with outstanding cellular uptake and cytotoxicity values, namely Dau[double bond, length as m-dash]Aoa-GFLG-GE11-PEG and Dau[double bond, length as m-dash]Aoa-GFLG-D4-G5-HbPG. According to our results, the PEG is suitable for longer targeting peptides (e.g. GE11), but the G5 spacer is not suitable irrespective of the length of the peptide because it may decrease the biological effect by increasing the flexibility of the polymer and shading of the targeting moiety. In contrast, the use of the hydrophilic hyperbranched polyglycerol (HbPG) is advantageous for short targeting peptides (e.g. D4) but only with a G5 spacer, which provides accessibility of the peptide for receptor binding and cellular uptake resulting in outstanding cytotoxicity."
REF00119	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>90% PSA decline	58.00%	%	NCT03511664	The primary objective of this study was to compare the two alternate primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) in patients with progressive prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who received 177Lu-PSMA-617 in addition to best supportive/best standard of care (BSC/BSoC) versus patients treated with best supportive/best standard of care alone.	Phase 3	Patients with metastatic castration-resistant prostate cancer treated with LuPSMA between December 2014 and July 2019.	.	.	.	.	.	.	.	"Median baseline PSA was 1000 (interquartile range 431-2151) ng/ml. PSA decline of at least 50% at 12 wk was achieved in 22 (58%) patients, while median time to pain progression was 8.3 (95% confidence interval [CI] 4.1-12.6) mouth. Median overall survival was 11.6 (95% CI 8.8-14.3) mouth."	.
REF00120	PDC_00027	Neuroendocrine tumour	Balb/c nude mice H1299-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Time of tumour stasis	16 Day	Day	.	.	.	.	Lung large cell carcinoma	H1299-7 cell	.	.	.	20 MBq	PET imaging studies	"Cell lines that expressed SSTR2 in vivo were implanted into nude mice and once the tumours became well-established the animals were injected intravenously with 20 MBq LuTate and the tumour response evaluated. Most tumour models showed similar robust growth kinetics but their response to LuTate varied widely. LuTate treatment of the H1299-7 and AR42J models induced tumour stasis for sixteen and twelve days post dosing, respectively, after which tumour growth rapidly resumed. In contrast, the D341 model, which showed similar SSTR2 expression and GaTate uptake to that of the AR42J model, was highly sensitive to LuTate with complete tumour regression observed for 65 days. The SK-N-BE(2) and BON tumour models which demonstrated low SSTR2 expression and GaTate binding were highly resistant to LuTate treatment."	.
REF00120	PDC_00027	Neuroendocrine tumour	Balb/c nude mice H1299-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Time of tumour stasis	12 Day	Day	.	.	.	.	Digestive system neoplasms	AR42J cell	.	.	.	20 MBq	PET imaging studies	"Cell lines that expressed SSTR2 in vivo were implanted into nude mice and once the tumours became well-established the animals were injected intravenously with 20 MBq LuTate and the tumour response evaluated. Most tumour models showed similar robust growth kinetics but their response to LuTate varied widely. LuTate treatment of the H1299-7 and AR42J models induced tumour stasis for sixteen and twelve days post dosing, respectively, after which tumour growth rapidly resumed. In contrast, the D341 model, which showed similar SSTR2 expression and GaTate uptake to that of the AR42J model, was highly sensitive to LuTate with complete tumour regression observed for 65 days. The SK-N-BE(2) and BON tumour models which demonstrated low SSTR2 expression and GaTate binding were highly resistant to LuTate treatment."	.
REF00120	PDC_00027	Neuroendocrine tumour	Balb/c nude mice H1299-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Time of tumour stasis	65 Day	Day	.	.	.	.	Medulloblastoma	D341 cell	.	.	.	20 MBq	PET imaging studies	"Cell lines that expressed SSTR2 in vivo were implanted into nude mice and once the tumours became well-established the animals were injected intravenously with 20 MBq LuTate and the tumour response evaluated. Most tumour models showed similar robust growth kinetics but their response to LuTate varied widely. LuTate treatment of the H1299-7 and AR42J models induced tumour stasis for sixteen and twelve days post dosing, respectively, after which tumour growth rapidly resumed. In contrast, the D341 model, which showed similar SSTR2 expression and GaTate uptake to that of the AR42J model, was highly sensitive to LuTate with complete tumour regression observed for 65 days. The SK-N-BE(2) and BON tumour models which demonstrated low SSTR2 expression and GaTate binding were highly resistant to LuTate treatment."	.
REF00121	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline rate	58%	%	.	.	.	22 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	First treatment cycle	.	.	"After the first treatment cycle, only 58% of the patients (n = 19) showed a decrease in serum PSA, and only 32% showed a decrease of more than 50%. After all treatment cycles were completed, 65% of the patients responded with a PSA drop greater than 50%. An even higher group of 84% responded with a general decrease in PSA levels. The highest reduction of PSA levels was observed from 139.1 to 0.24 ug/L (99.83%). Before PSMA RLT treatment, the mean serum PSA level was 258.12 ug/L (range, 0.42-3305.00 ug/L) and after 2 to 9 treatment cycles, it decreased to 79.61 ug/L (range, 0.24-869.10 ug/L)."	.
REF00121	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	32.00%	%	.	.	.	22 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	First treatment cycle	.	.	"After the first treatment cycle, only 58% of the patients (n = 19) showed a decrease in serum PSA, and only 32% showed a decrease of more than 50%. After all treatment cycles were completed, 65% of the patients responded with a PSA drop greater than 50%. An even higher group of 84% responded with a general decrease in PSA levels. The highest reduction of PSA levels was observed from 139.1 to 0.24 ug/L (99.83%). Before PSMA RLT treatment, the mean serum PSA level was 258.12 ug/L (range, 0.42-3305.00 ug/L) and after 2 to 9 treatment cycles, it decreased to 79.61 ug/L (range, 0.24-869.10 ug/L)."	.
REF00121	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline rate	84%	%	.	.	.	22 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	All treatment cycles	.	.	"After the first treatment cycle, only 58% of the patients (n = 19) showed a decrease in serum PSA, and only 32% showed a decrease of more than 50%. After all treatment cycles were completed, 65% of the patients responded with a PSA drop greater than 50%. An even higher group of 84% responded with a general decrease in PSA levels. The highest reduction of PSA levels was observed from 139.1 to 0.24 ug/L (99.83%). Before PSMA RLT treatment, the mean serum PSA level was 258.12 ug/L (range, 0.42-3305.00 ug/L) and after 2 to 9 treatment cycles, it decreased to 79.61 ug/L (range, 0.24-869.10 ug/L)."	.
REF00121	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	65.00%	%	.	.	.	22 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	All treatment cycles	.	.	"After the first treatment cycle, only 58% of the patients (n = 19) showed a decrease in serum PSA, and only 32% showed a decrease of more than 50%. After all treatment cycles were completed, 65% of the patients responded with a PSA drop greater than 50%. An even higher group of 84% responded with a general decrease in PSA levels. The highest reduction of PSA levels was observed from 139.1 to 0.24 ug/L (99.83%). Before PSMA RLT treatment, the mean serum PSA level was 258.12 ug/L (range, 0.42-3305.00 ug/L) and after 2 to 9 treatment cycles, it decreased to 79.61 ug/L (range, 0.24-869.10 ug/L)."	.
REF00121	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	32.30%	%	.	.	.	22 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	All treatment cycles	.	PET/CT assay	"Sixty-three TMVs were identified in the bone, lymph node, and liver tissue with an average reduction of 32.3%, 84.7%, and 72.9%, respectively. Absorbed doses per unit of administered activity for organs and lesions show good agreement with previous works (0.77, 0.71, and 0.27 mGy/MBq for parotid gland, kidneys, and liver as well as 4.38, 5.47, and 4.95 mGy/MBq for bone, lymph node, and liver malignancies, respectively)."	.
REF00121	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	84.70%	%	.	.	.	22 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	All treatment cycles	.	PET/CT assay	"Sixty-three TMVs were identified in the bone, lymph node, and liver tissue with an average reduction of 32.3%, 84.7%, and 72.9%, respectively. Absorbed doses per unit of administered activity for organs and lesions show good agreement with previous works (0.77, 0.71, and 0.27 mGy/MBq for parotid gland, kidneys, and liver as well as 4.38, 5.47, and 4.95 mGy/MBq for bone, lymph node, and liver malignancies, respectively)."	.
REF00121	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	72.90%	%	.	.	.	22 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	All treatment cycles	.	PET/CT assay	"Sixty-three TMVs were identified in the bone, lymph node, and liver tissue with an average reduction of 32.3%, 84.7%, and 72.9%, respectively. Absorbed doses per unit of administered activity for organs and lesions show good agreement with previous works (0.77, 0.71, and 0.27 mGy/MBq for parotid gland, kidneys, and liver as well as 4.38, 5.47, and 4.95 mGy/MBq for bone, lymph node, and liver malignancies, respectively)."	.
REF00122	PDC_00029	Metastatic castration-resistant prostate cancer	A 56-year-old man with metastatic castration-resistant prostate cancer.	Identified from the Human Clinical Data	High Expreesion	PSA decline	9.86 ng/mL	ng/mL	.	.	.	.	.	.	.	.	2 months after the t hird cycle of the therapy	5.92 GBq	.	"A 56-year-old man with metastatic castration-resistant prostate cancer underwent 3 cycles of radioligand therapy (RLT) with <sup>177</sup>Lu-prostate-specific membrane antigen (PSMA). The patient showed a dramatic response, a drop in prostate-specific antigen level from 11 ng/mL at baseline to 1.14 ng/mL at 2 months after the third cycle of the therapy, along with reduced bone pain."	.
REF00123	PDC_00027	Pancreatic neuroendocrine tumor	70-year-old woman treated by <sup>177</sup>Lu-DOTATATE injections for a metastatic recurrence of a pancreatic neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	SUV<sub>max</sub> decrease rate	58% &plusmn; 30%	%	.	.	.	.	.	.	.	.	3 injections at consecutive 2-month intervals	7.4 GBq	SPECT/CT assay	"Subclavian nodes and hepatic and bone lesions could be easily detected on the whole-body SPECT images (A), and the absolute quantification of these lesions demonstrated gradual decreases in SUV max values (B), leading to a global mean decrease of 58% &plusmn; 30% and thus giving evidence of marked decreases in lesion dosimetry."	.
REF00124	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	30%	%	.	.	.	"45 patients with advanced inoperable/metastatic neuroendocrine tumor (22 women, 23 men)."	.	.	.	.	2 to 7 cycles	27.0 GBq	68Ga-DOTATATE PET/CT assay	"Radiological response with the CT images of 68Ga-DOTANOC PET/CECT was assessed 8 to 12 weeks after the last treatment cycle. Three patients were lost to follow-up, and 2 other patients had nonmeasurable lesions on CT. Thus, according to RECIST 1.1, 40 patients had evaluable lesions, of which 12 patients (30%) had PR and 22 patients (55%) had SD, whereas disease progression was limited to 6 patients (15%). No case of CR was observed in our study cohort."	.
REF00124	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	55%	%	.	.	.	"45 patients with advanced inoperable/metastatic neuroendocrine tumor (22 women, 23 men)."	.	.	.	.	2 to 7 cycles	27.0 GBq	68Ga-DOTATATE PET/CT assay	"Radiological response with the CT images of 68Ga-DOTANOC PET/CECT was assessed 8 to 12 weeks after the last treatment cycle. Three patients were lost to follow-up, and 2 other patients had nonmeasurable lesions on CT. Thus, according to RECIST 1.1, 40 patients had evaluable lesions, of which 12 patients (30%) had PR and 22 patients (55%) had SD, whereas disease progression was limited to 6 patients (15%). No case of CR was observed in our study cohort."	.
REF00124	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	15%	%	.	.	.	"45 patients with advanced inoperable/metastatic neuroendocrine tumor (22 women, 23 men)."	.	.	.	.	2 to 7 cycles	27.0 GBq	68Ga-DOTATATE PET/CT assay	"Radiological response with the CT images of 68Ga-DOTANOC PET/CECT was assessed 8 to 12 weeks after the last treatment cycle. Three patients were lost to follow-up, and 2 other patients had nonmeasurable lesions on CT. Thus, according to RECIST 1.1, 40 patients had evaluable lesions, of which 12 patients (30%) had PR and 22 patients (55%) had SD, whereas disease progression was limited to 6 patients (15%). No case of CR was observed in our study cohort."	.
REF00129	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	42.00%	%	.	.	.	"19 patients with metastatic castration-resistant prostate cancer, median age 68.8 years (range: 56.9 - 83.3)."	.	.	.	.	Every 6-8 weeks	7.64 MBq per cycle	.	"Patients presented with bone, lymph node, and visceral metastases (89%, 68%, and 21%, respectively). All patients were pretreated with docetaxel, either abiraterone or enzalutamide, or both. Biochemical response in terms of PSA decline &ge;50 or &ge;30% was observed in 42% and 63%, respectively. There were significant correlations between PSA and PSMA mRNA expression, as well as tumor volumes (both MTV and TTV), AR-FL and AR-V7 mRNA expression. However, there was no correlation with response to PSMA treatment."	.
REF00129	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>20% PSA decline	63.00%	%	.	.	.	"19 patients with metastatic castration-resistant prostate cancer, median age 68.8 years (range: 56.9 - 83.3)."	.	.	.	.	Every 6-8 weeks	7.64 MBq per cycle	.	"Patients presented with bone, lymph node, and visceral metastases (89%, 68%, and 21%, respectively). All patients were pretreated with docetaxel, either abiraterone or enzalutamide, or both. Biochemical response in terms of PSA decline &ge;50 or &ge;30% was observed in 42% and 63%, respectively. There were significant correlations between PSA and PSMA mRNA expression, as well as tumor volumes (both MTV and TTV), AR-FL and AR-V7 mRNA expression. However, there was no correlation with response to PSMA treatment."	.
REF00130	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	46.00%	%	.	.	.	Patients with metastatic castration-resistant prostate cance treated with LuPSMA between December 2014 and October 2018.	.	.	.	.	3 cycles	19.3 GBq (cumulated activity)	.	.	.
REF00132	PDC_00027	Head and neck paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD) + Progressive disease (PD)	60%	%	.	.	.	7 patients with head and neck paraganglioma treated with PPRT between May 2014 and October 2016.	.	.	.	.	Underwent 3-5 cycles in 8- to 10-week intervals between may 2014 and october 2016	7.2 &plusmn; 0.4 GBq	PET/CT assay	Overall results for PRRT in paraganglioma and pheochromocytoma are promising with response rates (SD and PR) of >60%.	.
REF00133	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	62%	%	.	.	.	Metastatic castration-resistant prostate cancer patients.	.	.	.	.	.	.	.	"One of the earliest experiences with <sup>177</sup>Lu-PSMA-617 radioligand therapy (RLT) was described by Ahmadzadehfar et al. in 2015. Ten patients with mCRPC were recruited to undergo <sup>177</sup>Lu-PSMA-617 RLT and received one cycle of therapy (dose 6 GBq). At eight-week follow-up, 70% (7/10) experienced PSA decline, and 50% (5/10) experienced >50% decline in PSA levels. After those initial encouraging results, in a follow-up study with an expanded cohort, 24 patients with progressive mCRPC underwent <sup>177</sup>Lu-PSMA-617 RLT. After one cycle, 79.1% (19/24) showed a decline in PSA levels; 41.7% (10/24) showed >50% decline. Twenty-two out of the 24 patients were selected for a second cycle, and 68.2% (15/22) had a PSA decline, with 13 (59%) experiencing >50% decline. Since then, numerous retrospective studies with larger groups of patients have been published by the same group. In 2017, Ahmadzadehfar et al. reported a cohort of 52 patients who each received between three and six cycles of therapy (mean: 3.6 cycles, mean dose: 6 GBq). Dosing was administered in eight-week intervals and the median cumulative dose was 18.5 GBq. Of note, 80.8% (42/52) experienced a PSA decline eight weeks after the first cycle. Median overall survival was 60 weeks, with patients who had PSA responses having significantly longer survival compared to those who did not (68 vs. 33 weeks). In a cohort of 99 patients who received between one to four cycles of therapy (mean: 1.7 cycles) with 8-12 week intervals, 65.6% (45/99) had PSA response after the first cycle. In a cohort of 104 patients, described in 2018, 67.3% (70/104) experienced a PSA decline after one cycle of therapy. Patients underwent an average of 3.4 cycles of therapy, with eight-week intervals. The average dose was 6.1 GBq per cycle and 18.8 GBq cumulatively. The median overall survival was 56 weeks; again, those who responded had longer survival (62.9 vs. 47 weeks)."	.
REF00133	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	58.00%	%	.	.	.	Metastatic castration-resistant prostate cancer patients.	.	.	.	.	.	.	.	"One of the earliest experiences with <sup>177</sup>Lu-PSMA-617 radioligand therapy (RLT) was described by Ahmadzadehfar et al. in 2015. Ten patients with mCRPC were recruited to undergo <sup>177</sup>Lu-PSMA-617 RLT and received one cycle of therapy (dose 6 GBq). At eight-week follow-up, 70% (7/10) experienced PSA decline, and 50% (5/10) experienced >50% decline in PSA levels. After those initial encouraging results, in a follow-up study with an expanded cohort, 24 patients with progressive mCRPC underwent <sup>177</sup>Lu-PSMA-617 RLT. After one cycle, 79.1% (19/24) showed a decline in PSA levels; 41.7% (10/24) showed >50% decline. Twenty-two out of the 24 patients were selected for a second cycle, and 68.2% (15/22) had a PSA decline, with 13 (59%) experiencing >50% decline. Since then, numerous retrospective studies with larger groups of patients have been published by the same group. In 2017, Ahmadzadehfar et al. reported a cohort of 52 patients who each received between three and six cycles of therapy (mean: 3.6 cycles, mean dose: 6 GBq). Dosing was administered in eight-week intervals and the median cumulative dose was 18.5 GBq. Of note, 80.8% (42/52) experienced a PSA decline eight weeks after the first cycle. Median overall survival was 60 weeks, with patients who had PSA responses having significantly longer survival compared to those who did not (68 vs. 33 weeks). In a cohort of 99 patients who received between one to four cycles of therapy (mean: 1.7 cycles) with 8-12 week intervals, 65.6% (45/99) had PSA response after the first cycle. In a cohort of 104 patients, described in 2018, 67.3% (70/104) experienced a PSA decline after one cycle of therapy. Patients underwent an average of 3.4 cycles of therapy, with eight-week intervals. The average dose was 6.1 GBq per cycle and 18.8 GBq cumulatively. The median overall survival was 56 weeks; again, those who responded had longer survival (62.9 vs. 47 weeks)."	.
REF00134	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	56.70%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6weeks interval.	.	.	.	.	4 cycles at 6-week intervals	7.5 GBq	.	"The first prospective study published by the Australian group (LuPSMA trial) was a single-center, single-arm phase 2 study in 30 mCRPC patients who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6 weeks interval. Seventeen (56.7%) of the patients reported &ge;50% decline in PSA. Four patients (13%) reported relevant grade 3-4 thrombocytopenia."	.
REF00134	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 3/4 thrombocytopenia	13%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6weeks interval.	.	.	.	.	4 cycles at 6-week intervals	7.5 GBq	.	"The first prospective study published by the Australian group (LuPSMA trial) was a single-center, single-arm phase 2 study in 30 mCRPC patients who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6 weeks interval. Seventeen (56.7%) of the patients reported &ge;50% decline in PSA. Four patients (13%) reported relevant grade 3-4 thrombocytopenia."	.
REF00134	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	64.00%	%	.	.	.	50 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles at 6-week intervals	7.5 GBq	.	"A further extension of this study with 50 patients recently reported &ge;50% decrease in PSA in 64% of patients and grade 3-4 thrombocytopenia or anemia in 10% of the patients. Median progression-free survival (PFS) and overall survival (OS) was 6.9 months and 13.3 months, respectively."	.
REF00134	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 3/4 thrombocytopenia/anemia	10%	%	.	.	.	50 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles at 6-week intervals	7.5 GBq	.	"A further extension of this study with 50 patients recently reported &ge;50% decrease in PSA in 64% of patients and grade 3-4 thrombocytopenia or anemia in 10% of the patients. Median progression-free survival (PFS) and overall survival (OS) was 6.9 months and 13.3 months, respectively."	.
REF00134	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	6.9 months	months	.	.	.	50 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles at 6-week intervals	7.5 GBq	.	"A further extension of this study with 50 patients recently reported &ge;50% decrease in PSA in 64% of patients and grade 3-4 thrombocytopenia or anemia in 10% of the patients. Median progression-free survival (PFS) and overall survival (OS) was 6.9 months and 13.3 months, respectively."	.
REF00134	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	13.3 months	months	.	.	.	50 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles at 6-week intervals	7.5 GBq	.	"A further extension of this study with 50 patients recently reported &ge;50% decrease in PSA in 64% of patients and grade 3-4 thrombocytopenia or anemia in 10% of the patients. Median progression-free survival (PFS) and overall survival (OS) was 6.9 months and 13.3 months, respectively."	.
REF00134	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>90% PSA decline	38.00%	%	NCT03042312	"This was an open-label, multicenter, prospective trial to assess safety and efficacy of 177Lu-PSMA-617 in patients with metastatic castration resistant prostate cancer."	Phase 2	64 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Up to 4 cycles at every 8 &plusmn; 1 weeks	6.0/7.4 GBq	.	"An investigator-initiated prospective open-label bi-centric single-arm phase 2 trial RESIST-PC (NCT03042312) randomized 64 mCRPC patients in two Lu-177 PSMA-617 activity groups (6.0 or 7.4 GBq) with up to 4 cycles at every 8 &plusmn; 1 weeks. PSA decline of &ge;50% was seen in 38% of the patients, and the best PSA response occurred after 3 cycles."	.
REF00135	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	73.00%	%	.	.	.	"30 patients undergoing <sup>177</sup>Lu-PSMA-617 therapy from 2014 to 2016 (age range 50-87 years, median 73.5 years)."	.	.	.	.	.	.	.	"Most patients underwent three treatment cycles (n=12); at least 2 cycles (n=6) or at most 8 cycles (n=1) were performed. Out of 30 cases, PSA response after the first cycle was observed in 73% (n=22). Compared to baseline, QoL was significantly improved at 2-month follow-up revealing increase in global health status (p=0.025), role functioning (p=0.017) and emotional functioning (0.010), and decrease in pain (p=0.033). Global health status variation can be explained up to 20.5% by response in PSA (p=0.012), this improved with PSA reduction."	.
REF00136	PDC_00027	Midgut neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	28.5 months	months	.	.	.	Patients with midgut neuroendocrine tumour treated with <sup>177</sup>Lu-Dotatate.	.	.	.	.	.	.	.	"The approval of <sup>177</sup>Lu-Dotatate was based on the findings of the phase III NETTER-1 trial, which showed that for patients with midgut (jejunum, ileum, appendix and proximal colon) NETs, the use of <sup>177</sup>Lu-Dotatate (plus octreotide long-acting repeatable [LAR] 30 mg for symptom control) led to a significant gain in both progression-free survival (PFS), overall survival (OS) and quality of life relative to BSC involving octreotide LAR 60 mg Findings from the pivotal phase III NETTER-1 trial were supported by data from the ERASMUS study, in which midgut-NET patients treated with <sup>177</sup>Lu-Dotatate had a median (95% CI) PFS and OS of 28.5 (23.9-33.3) months and 54.9 (47.5-63.2) months, respectively."	.
REF00136	PDC_00027	Midgut neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	54.9 months	months	.	.	.	Patients with midgut neuroendocrine tumour treated with <sup>177</sup>Lu-Dotatate.	.	.	.	.	.	.	.	"The approval of <sup>177</sup>Lu-Dotatate was based on the findings of the phase III NETTER-1 trial, which showed that for patients with midgut (jejunum, ileum, appendix and proximal colon) NETs, the use of <sup>177</sup>Lu-Dotatate (plus octreotide long-acting repeatable [LAR] 30 mg for symptom control) led to a significant gain in both progression-free survival (PFS), overall survival (OS) and quality of life relative to BSC involving octreotide LAR 60 mg Findings from the pivotal phase III NETTER-1 trial were supported by data from the ERASMUS study, in which midgut-NET patients treated with <sup>177</sup>Lu-Dotatate had a median (95% CI) PFS and OS of 28.5 (23.9-33.3) months and 54.9 (47.5-63.2) months, respectively."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	45.70%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	"Long-term outcome (follow-up ranging from 4 to 97.6 months; median period:46 months following first <sup>177</sup>Lu-DOTATATE PRRT) results showed, (i) on symptomatic response evaluation scale, complete response (CR) in 214 patients (45.7%), partial response (PR) in 108 (23.1%), stable disease (SD) in 118 (25.2%), progressive disease (PD) in 28 (6%)."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	23.10%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	"Long-term outcome (follow-up ranging from 4 to 97.6 months; median period:46 months following first <sup>177</sup>Lu-DOTATATE PRRT) results showed, (i) on symptomatic response evaluation scale, complete response (CR) in 214 patients (45.7%), partial response (PR) in 108 (23.1%), stable disease (SD) in 118 (25.2%), progressive disease (PD) in 28 (6%)."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	25.20%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	"Long-term outcome (follow-up ranging from 4 to 97.6 months; median period:46 months following first <sup>177</sup>Lu-DOTATATE PRRT) results showed, (i) on symptomatic response evaluation scale, complete response (CR) in 214 patients (45.7%), partial response (PR) in 108 (23.1%), stable disease (SD) in 118 (25.2%), progressive disease (PD) in 28 (6%)."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	6%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	"Long-term outcome (follow-up ranging from 4 to 97.6 months; median period:46 months following first <sup>177</sup>Lu-DOTATATE PRRT) results showed, (i) on symptomatic response evaluation scale, complete response (CR) in 214 patients (45.7%), partial response (PR) in 108 (23.1%), stable disease (SD) in 118 (25.2%), progressive disease (PD) in 28 (6%)."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	12%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	"Biochemical response evaluation showed CR in 52 (12%), PR in 172 (40%), SD in 161 (38%), and PD in 42 patients (10%)."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	40%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	"Biochemical response evaluation showed CR in 52 (12%), PR in 172 (40%), SD in 161 (38%), and PD in 42 patients (10%)."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	38%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	"Biochemical response evaluation showed CR in 52 (12%), PR in 172 (40%), SD in 161 (38%), and PD in 42 patients (10%)."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	10%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	"Biochemical response evaluation showed CR in 52 (12%), PR in 172 (40%), SD in 161 (38%), and PD in 42 patients (10%)."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	6%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	PERCIST criteria assay	"Molecular imaging response (by PERCIST criteria) showed CR in 29 (6%), PR in 116 (25%), SD in 267 (57%) and PD in 56 (12%) patients."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	25%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	PERCIST criteria assay	"Molecular imaging response (by PERCIST criteria) showed CR in 29 (6%), PR in 116 (25%), SD in 267 (57%) and PD in 56 (12%) patients."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	57%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	PERCIST criteria assay	"Molecular imaging response (by PERCIST criteria) showed CR in 29 (6%), PR in 116 (25%), SD in 267 (57%) and PD in 56 (12%) patients."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	12%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	PERCIST criteria assay	"Molecular imaging response (by PERCIST criteria) showed CR in 29 (6%), PR in 116 (25%), SD in 267 (57%) and PD in 56 (12%) patients."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	3%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	"On RECIST 1.1 criteria, CR was observed in 14 patients (3%), PR in 126 patients (27%), SD in 282 patients (60%) and PD in 46 patients (10%)."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	27%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	"On RECIST 1.1 criteria, CR was observed in 14 patients (3%), PR in 126 patients (27%), SD in 282 patients (60%) and PD in 46 patients (10%)."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	60%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	"On RECIST 1.1 criteria, CR was observed in 14 patients (3%), PR in 126 patients (27%), SD in 282 patients (60%) and PD in 46 patients (10%)."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	10%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	"On RECIST 1.1 criteria, CR was observed in 14 patients (3%), PR in 126 patients (27%), SD in 282 patients (60%) and PD in 46 patients (10%)."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	71.10%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	The median PFS and OS were not reached at a median follow-up of 46 months. Observed PFS and OS at 7 years were 71.1% 95% CI (62.4-79.7%) and 79.4% 95% CI (71.4-86.9%) respectively.	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	79.40%	%	.	.	.	468 patients with metastatic/advanced neuroendocrine tumor.	.	.	.	.	At least two cycles at 10-12 weeks interval	5.55 to 7.4 GBq per patient	.	The median PFS and OS were not reached at a median follow-up of 46 months. Observed PFS and OS at 7 years were 71.1% 95% CI (62.4-79.7%) and 79.4% 95% CI (71.4-86.9%) respectively.	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	93.50%	%	.	.	.	29 patients with neuroendocrine tumour with progressive disease at the initiation point of PRRT.	.	.	.	.	.	.	.	"On a separate sub-analysis of 322 NET patients with progressive disease at the initiation point of PRRT, overall response rates (CR + PR + SD) were 93.5%, 88.5%, 89.1 and 87.9% on symptomatic, biochemical, RECIST 1.1 and PERCIST criteria and PFS and OS at 7 years 68.3% and 79.2%, respectively."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	88.50%	%	.	.	.	29 patients with neuroendocrine tumour with progressive disease at the initiation point of PRRT.	.	.	.	.	.	.	.	"On a separate sub-analysis of 322 NET patients with progressive disease at the initiation point of PRRT, overall response rates (CR + PR + SD) were 93.5%, 88.5%, 89.1 and 87.9% on symptomatic, biochemical, RECIST 1.1 and PERCIST criteria and PFS and OS at 7 years 68.3% and 79.2%, respectively."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	89.10%	%	.	.	.	29 patients with neuroendocrine tumour with progressive disease at the initiation point of PRRT.	.	.	.	.	.	.	.	"On a separate sub-analysis of 322 NET patients with progressive disease at the initiation point of PRRT, overall response rates (CR + PR + SD) were 93.5%, 88.5%, 89.1 and 87.9% on symptomatic, biochemical, RECIST 1.1 and PERCIST criteria and PFS and OS at 7 years 68.3% and 79.2%, respectively."	.
REF00137	PDC_00027	Metastatic/Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	87.90%	%	.	.	.	29 patients with neuroendocrine tumour with progressive disease at the initiation point of PRRT.	.	.	.	.	.	.	.	"On a separate sub-analysis of 322 NET patients with progressive disease at the initiation point of PRRT, overall response rates (CR + PR + SD) were 93.5%, 88.5%, 89.1 and 87.9% on symptomatic, biochemical, RECIST 1.1 and PERCIST criteria and PFS and OS at 7 years 68.3% and 79.2%, respectively."	.
REF00138	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	80.30%	%	.	.	.	61 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	T hree cycles at four weekly intervals	Mean 7321 &plusmn; 592 MBq	.	"Forty-nine (80.3%) patients demonstrated a therapy response in terms of any PSA decline, while 21 (19.7%) patients showed increase or no changes in their PSA levels."	.
REF00138	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Rate of PSA increase	19.70%	%	.	.	.	61 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	T hree cycles at four weekly intervals	Mean 7321 &plusmn; 592 MBq	.	"Forty-nine (80.3%) patients demonstrated a therapy response in terms of any PSA decline, while 21 (19.7%) patients showed increase or no changes in their PSA levels."	.
REF00139	PDC_00027	Negative progressive/Symptomatic locally advanced/Metastatic paragangliomas	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	67%	%	.	.	.	9 patients with paragangliomas.	.	.	.	.	&ge; 4cycles	> 22.2 GBq)	.	.	.
REF00139	PDC_00027	Negative progressive/Symptomatic locally advanced/Metastatic paragangliomas	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	63%	%	.	.	.	9 patients with paragangliomas.	.	.	.	.	&ge; 4cycles	> 22.2 GBq)	.	.	.
REF00139	PDC_00027	Negative progressive/Symptomatic locally advanced/Metastatic paragangliomas	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	65%	%	.	.	.	9 patients with paragangliomas.	.	.	.	.	&ge; 4cycles	> 22.2 GBq)	.	.	.
REF00141	PDC_00027	Inoperable grade I/II neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 fatigue	87.10%	%	.	.	.	31 patients treated using the fast-infusion protocol.	.	.	.	.	> 5 min	7.4 GBq	.	"Thirty-one patients, treated using the fast-infusion protocol, were included. Clinical toxicity mainly consisted of grade 1/2 fatigue (87.1%) and grade 1 nausea or vomiting (67.7%) during follow-up. No acute or long-term clinical toxicity possibly related to the fast-infusion protocol was reported. Grade 3/4 hematologic toxicity occurred after PRRT in 1 patient (3.2%). No grade 3/4 renal toxicity occurred. The laboratory experiment showed that when using the gravity method for infusion, half of the activity is infused after 3.5 min, and 95% is infused within 15 min."	.
REF00141	PDC_00027	Inoperable grade I/II neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 nausea	67.70%	%	.	.	.	31 patients treated using the fast-infusion protocol.	.	.	.	.	> 5 min	7.4 GBq	.	"Thirty-one patients, treated using the fast-infusion protocol, were included. Clinical toxicity mainly consisted of grade 1/2 fatigue (87.1%) and grade 1 nausea or vomiting (67.7%) during follow-up. No acute or long-term clinical toxicity possibly related to the fast-infusion protocol was reported. Grade 3/4 hematologic toxicity occurred after PRRT in 1 patient (3.2%). No grade 3/4 renal toxicity occurred. The laboratory experiment showed that when using the gravity method for infusion, half of the activity is infused after 3.5 min, and 95% is infused within 15 min."	.
REF00141	PDC_00027	Inoperable grade I/II neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 3/4 hematologic toxicity	3.20%	%	.	.	.	31 patients treated using the fast-infusion protocol.	.	.	.	.	> 5 min	7.4 GBq	.	"Thirty-one patients, treated using the fast-infusion protocol, were included. Clinical toxicity mainly consisted of grade 1/2 fatigue (87.1%) and grade 1 nausea or vomiting (67.7%) during follow-up. No acute or long-term clinical toxicity possibly related to the fast-infusion protocol was reported. Grade 3/4 hematologic toxicity occurred after PRRT in 1 patient (3.2%). No grade 3/4 renal toxicity occurred. The laboratory experiment showed that when using the gravity method for infusion, half of the activity is infused after 3.5 min, and 95% is infused within 15 min."	.
REF00142	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Malondialdehyde increase rate	0.55 &micro;M	&micro;M	.	.	.	"Prostate cancer and neuroendocrine tumor patients referred to therapy with <sup>177</sup>Lu-PSMA and <sup>177</sup>Lu-DOTATATE, respectively."	.	.	.	.	48 h	5.5 GBq	.	"In total, 61 RNT cycles were evaluated in 34 patients with age of 65 &plusmn; 2.83 (median &plusmn; SE) years (range of 27-99); this total included 20 (59%) prostate cancer patients [35 cycles (57.4%)] and 14 patients (41%) with NET [26 cycles (42.6%)]. Of the 61 evaluated cycles, 27 cycles were given in the control group and 34 cycles were given in the intervention group. The serum level of MDA was significantly increased after treatment compared to before treatment (P = 0.02) in the control group, while no significant change in the serum level of MDA was observed in the intervention group (P = 0.52). The serum level of GSH was insignificantly decreased after treatment compared to before treatment in the control group and slightly increased after treatment in the intervention group (P > 0.05). The serum level of glutathione reductase was insignificantly increased in all groups of patients after treatment (P > 0.05)."	"Although RNT with <sup>177</sup>Lu-DOTATATE/PSMA is known as a novel and effective therapy option for cancer that significantly improves the quality of life and survival of patients, it may have acute or chronic side effects. Therefore, any method that can ameliorate these side effects is useful in the RNT process. For this purpose, a few clinical studies have reported that antioxidants as free radical scavengers such as amifostine and vitamins C and E can reduce radioiodine-related side effects, particularly in salivary glands in thyroid cancer patients."
REF00142	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Malondialdehyde increase rate	0.44 &micro;M	&micro;M	.	.	.	"Prostate cancer and neuroendocrine tumor patients referred to therapy with <sup>177</sup>Lu-PSMA and <sup>177</sup>Lu-DOTATATE, respectively."	.	.	.	.	48 h	7.4 GBq	.	"In total, 61 RNT cycles were evaluated in 34 patients with age of 65 &plusmn; 2.83 (median &plusmn; SE) years (range of 27-99); this total included 20 (59%) prostate cancer patients [35 cycles (57.4%)] and 14 patients (41%) with NET [26 cycles (42.6%)]. Of the 61 evaluated cycles, 27 cycles were given in the control group and 34 cycles were given in the intervention group. The serum level of MDA was significantly increased after treatment compared to before treatment (P = 0.02) in the control group, while no significant change in the serum level of MDA was observed in the intervention group (P = 0.52). The serum level of GSH was insignificantly decreased after treatment compared to before treatment in the control group and slightly increased after treatment in the intervention group (P > 0.05). The serum level of glutathione reductase was insignificantly increased in all groups of patients after treatment (P > 0.05)."	"Although RNT with <sup>177</sup>Lu-DOTATATE/PSMA is known as a novel and effective therapy option for cancer that significantly improves the quality of life and survival of patients, it may have acute or chronic side effects. Therefore, any method that can ameliorate these side effects is useful in the RNT process. For this purpose, a few clinical studies have reported that antioxidants as free radical scavengers such as amifostine and vitamins C and E can reduce radioiodine-related side effects, particularly in salivary glands in thyroid cancer patients."
REF00142	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Glutathione increase rate	0.016 mg/mL	mg/mL	.	.	.	"Prostate cancer and neuroendocrine tumor patients referred to therapy with <sup>177</sup>Lu-PSMA and <sup>177</sup>Lu-DOTATATE, respectively."	.	.	.	.	48 h	5.5 GBq	.	"In total, 61 RNT cycles were evaluated in 34 patients with age of 65 &plusmn; 2.83 (median &plusmn; SE) years (range of 27-99); this total included 20 (59%) prostate cancer patients [35 cycles (57.4%)] and 14 patients (41%) with NET [26 cycles (42.6%)]. Of the 61 evaluated cycles, 27 cycles were given in the control group and 34 cycles were given in the intervention group. The serum level of MDA was significantly increased after treatment compared to before treatment (P = 0.02) in the control group, while no significant change in the serum level of MDA was observed in the intervention group (P = 0.52). The serum level of GSH was insignificantly decreased after treatment compared to before treatment in the control group and slightly increased after treatment in the intervention group (P > 0.05). The serum level of glutathione reductase was insignificantly increased in all groups of patients after treatment (P > 0.05)."	"In biological systems, antioxidants such as catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase are responsible for the elimination or reduction of the adverse effects of ROS, that is, they prevent or reduce ROS generation. Dietary antioxidants, such as vitamins E, A, and C, and anthocyanins and polyphenols have a role in the protection of cells against ROS damage."
REF00142	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Glutathione decrease rate	0.001 mg/mL	mg/mL	.	.	.	"Prostate cancer and neuroendocrine tumor patients referred to therapy with <sup>177</sup>Lu-PSMA and <sup>177</sup>Lu-DOTATATE, respectively."	.	.	.	.	48 h	7.4 GBq	.	"In total, 61 RNT cycles were evaluated in 34 patients with age of 65 &plusmn; 2.83 (median &plusmn; SE) years (range of 27-99); this total included 20 (59%) prostate cancer patients [35 cycles (57.4%)] and 14 patients (41%) with NET [26 cycles (42.6%)]. Of the 61 evaluated cycles, 27 cycles were given in the control group and 34 cycles were given in the intervention group. The serum level of MDA was significantly increased after treatment compared to before treatment (P = 0.02) in the control group, while no significant change in the serum level of MDA was observed in the intervention group (P = 0.52). The serum level of GSH was insignificantly decreased after treatment compared to before treatment in the control group and slightly increased after treatment in the intervention group (P > 0.05). The serum level of glutathione reductase was insignificantly increased in all groups of patients after treatment (P > 0.05)."	.
REF00142	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Glutathione reductase increase rate	6.6 nmol/min/mg	nmol/min/mg	.	.	.	"Prostate cancer and neuroendocrine tumor patients referred to therapy with <sup>177</sup>Lu-PSMA and <sup>177</sup>Lu-DOTATATE, respectively."	.	.	.	.	48 h	5.5 GBq	.	"In total, 61 RNT cycles were evaluated in 34 patients with age of 65 &plusmn; 2.83 (median &plusmn; SE) years (range of 27-99); this total included 20 (59%) prostate cancer patients [35 cycles (57.4%)] and 14 patients (41%) with NET [26 cycles (42.6%)]. Of the 61 evaluated cycles, 27 cycles were given in the control group and 34 cycles were given in the intervention group. The serum level of MDA was significantly increased after treatment compared to before treatment (P = 0.02) in the control group, while no significant change in the serum level of MDA was observed in the intervention group (P = 0.52). The serum level of GSH was insignificantly decreased after treatment compared to before treatment in the control group and slightly increased after treatment in the intervention group (P > 0.05). The serum level of glutathione reductase was insignificantly increased in all groups of patients after treatment (P > 0.05)."	"Vitamin C as a water-soluble vitamin is the reduced form of ascorbic acid. No significant adverse effect of taking high doses of vitamin C (over 2000 mg/day) has been reported due to the water-soluble feature of vitamin C. Vitamin C directly reacts with hydroxy, alkoxyl, and lipid peroxyl radicals and converts them to alcohol, water, and hydroperoxide lipid, respectively. It has been shown that taking vitamin C before radioiodine therapy can ameliorate the oxidative stress effect of radioiodine. The radioprotective effects of vitamin C are mainly due to its free radical scavenging activity."
REF00142	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Glutathione reductase increase rate	4.04 nmol/min/mg	nmol/min/mg	.	.	.	"Prostate cancer and neuroendocrine tumor patients referred to therapy with <sup>177</sup>Lu-PSMA and <sup>177</sup>Lu-DOTATATE, respectively."	.	.	.	.	48 h	7.4 GBq	.	"In total, 61 RNT cycles were evaluated in 34 patients with age of 65 &plusmn; 2.83 (median &plusmn; SE) years (range of 27-99); this total included 20 (59%) prostate cancer patients [35 cycles (57.4%)] and 14 patients (41%) with NET [26 cycles (42.6%)]. Of the 61 evaluated cycles, 27 cycles were given in the control group and 34 cycles were given in the intervention group. The serum level of MDA was significantly increased after treatment compared to before treatment (P = 0.02) in the control group, while no significant change in the serum level of MDA was observed in the intervention group (P = 0.52). The serum level of GSH was insignificantly decreased after treatment compared to before treatment in the control group and slightly increased after treatment in the intervention group (P > 0.05). The serum level of glutathione reductase was insignificantly increased in all groups of patients after treatment (P > 0.05)."	.
REF00143	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>90% PSA decline	33.00%	%	.	.	.	45 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"164 cycles of rnt, every 6-8 weeks"	.	.	"Forty-five patients were treated with total of 164 cycles of RNT. Fifteen patients (33%) had PSA decline of &ge;50%, 23 patients (51%) showed any PSA decline and 20 patients (44%) showed PSA increase of &ge;25%. Median OS and PFS were 17,1 months and 7,4 months. Patients had any or &ge;50% PSA response after the first cycle, lower initial ALP (<120U/L) had longer OS and PFS. Patients had normal Hb showed longer OS and patients had lower initial PSA (<51ng/mL) had longer PFS. Patients had PSA progression of &ge;25% had shorter OS and PFS."	.
REF00143	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	51%	%	.	.	.	45 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"164 cycles of rnt, every 6-8 weeks"	.	.	"Forty-five patients were treated with total of 164 cycles of RNT. Fifteen patients (33%) had PSA decline of &ge;50%, 23 patients (51%) showed any PSA decline and 20 patients (44%) showed PSA increase of &ge;25%. Median OS and PFS were 17,1 months and 7,4 months. Patients had any or &ge;50% PSA response after the first cycle, lower initial ALP (<120U/L) had longer OS and PFS. Patients had normal Hb showed longer OS and patients had lower initial PSA (<51ng/mL) had longer PFS. Patients had PSA progression of &ge;25% had shorter OS and PFS."	.
REF00143	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>25% PSA increase	44.00%	%	.	.	.	45 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"164 cycles of rnt, every 6-8 weeks"	.	.	"Forty-five patients were treated with total of 164 cycles of RNT. Fifteen patients (33%) had PSA decline of &ge;50%, 23 patients (51%) showed any PSA decline and 20 patients (44%) showed PSA increase of &ge;25%. Median OS and PFS were 17,1 months and 7,4 months. Patients had any or &ge;50% PSA response after the first cycle, lower initial ALP (<120U/L) had longer OS and PFS. Patients had normal Hb showed longer OS and patients had lower initial PSA (<51ng/mL) had longer PFS. Patients had PSA progression of &ge;25% had shorter OS and PFS."	.
REF00143	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	7.4 months	months	.	.	.	45 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"164 cycles of rnt, every 6-8 weeks"	.	.	"Forty-five patients were treated with total of 164 cycles of RNT. Fifteen patients (33%) had PSA decline of &ge;50%, 23 patients (51%) showed any PSA decline and 20 patients (44%) showed PSA increase of &ge;25%. Median OS and PFS were 17,1 months and 7,4 months. Patients had any or &ge;50% PSA response after the first cycle, lower initial ALP (<120U/L) had longer OS and PFS. Patients had normal Hb showed longer OS and patients had lower initial PSA (<51ng/mL) had longer PFS. Patients had PSA progression of &ge;25% had shorter OS and PFS."	.
REF00143	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	17.1 months	months	.	.	.	45 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"164 cycles of rnt, every 6-8 weeks"	.	.	"Forty-five patients were treated with total of 164 cycles of RNT. Fifteen patients (33%) had PSA decline of &ge;50%, 23 patients (51%) showed any PSA decline and 20 patients (44%) showed PSA increase of &ge;25%. Median OS and PFS were 17,1 months and 7,4 months. Patients had any or &ge;50% PSA response after the first cycle, lower initial ALP (<120U/L) had longer OS and PFS. Patients had normal Hb showed longer OS and patients had lower initial PSA (<51ng/mL) had longer PFS. Patients had PSA progression of &ge;25% had shorter OS and PFS."	.
REF00144	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	10%	%	.	.	.	10 patients with metastatic castration-resistant prostate cancer and with visceral metastasis.	.	.	.	.	One cycle	4.88 GBq	Prostate-specific antigen (PSA) response assessment assay	"Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of <sup>177</sup>Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen."	Lutetium-177-PSMA was a reasonable palliative treatment option with limited toxicity for these end-stage mCRPC patients with visceral metastasis with adequate PSA stabilization. A synergistic drug amalgamation may be an ideal way to boost the outcome in the future.
REF00144	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	60%	%	.	.	.	10 patients with metastatic castration-resistant prostate cancer and with visceral metastasis.	.	.	.	.	One cycle	4.88 GBq	Prostate-specific antigen (PSA) response assessment assay	"Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of <sup>177</sup>Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen."	Lutetium-177-PSMA was a reasonable palliative treatment option with limited toxicity for these end-stage mCRPC patients with visceral metastasis with adequate PSA stabilization. A synergistic drug amalgamation may be an ideal way to boost the outcome in the future.
REF00144	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	30%	%	.	.	.	10 patients with metastatic castration-resistant prostate cancer and with visceral metastasis.	.	.	.	.	One cycle	4.88 GBq	Prostate-specific antigen (PSA) response assessment assay	"Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of <sup>177</sup>Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen."	Lutetium-177-PSMA was a reasonable palliative treatment option with limited toxicity for these end-stage mCRPC patients with visceral metastasis with adequate PSA stabilization. A synergistic drug amalgamation may be an ideal way to boost the outcome in the future.
REF00144	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Visual relief rate	40%	%	.	.	.	10 patients with metastatic castration-resistant prostate cancer and with visceral metastasis.	.	.	.	.	One cycle	4.88 GBq	.	"Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of <sup>177</sup>Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen."	Lutetium-177-PSMA was a reasonable palliative treatment option with limited toxicity for these end-stage mCRPC patients with visceral metastasis with adequate PSA stabilization. A synergistic drug amalgamation may be an ideal way to boost the outcome in the future.
REF00144	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Pain relief rate	50%	%	.	.	.	10 patients with metastatic castration-resistant prostate cancer and with visceral metastasis.	.	.	.	.	One cycle	4.88 GBq	.	"Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of <sup>177</sup>Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen."	Lutetium-177-PSMA was a reasonable palliative treatment option with limited toxicity for these end-stage mCRPC patients with visceral metastasis with adequate PSA stabilization. A synergistic drug amalgamation may be an ideal way to boost the outcome in the future.
REF00144	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	24 weeks	weeks	.	.	.	10 patients with metastatic castration-resistant prostate cancer and with visceral metastasis.	.	.	.	.	One cycle	4.88 GBq	.	"Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of <sup>177</sup>Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen."	Lutetium-177-PSMA was a reasonable palliative treatment option with limited toxicity for these end-stage mCRPC patients with visceral metastasis with adequate PSA stabilization. A synergistic drug amalgamation may be an ideal way to boost the outcome in the future.
REF00144	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 anemia	30%	%	.	.	.	10 patients with metastatic castration-resistant prostate cancer and with visceral metastasis.	.	.	.	.	One cycle	4.88 GBq	.	"Liver (80%), lung (30%), adrenal (10%), and peritoneum (10%) were the sites of visceral metastasis in our study. On PSA response assessment, 10%, 60%, and 30% of the patients had partial response, stable disease, and progressive disease, respectively. Forty percent of the patients had improvement in the VAS, while 50% had improvement in the AQS score. Median PFS was 24 weeks in our study. A cut-off of 4.88GBq of <sup>177</sup>Lu-PSMA was the best-predicted progression with 66.67% sensitivity and 100% specificity on ROC analysis. Thirty percent of the patients showed grade 3 anemia. No other significant toxicity was seen."	Lutetium-177-PSMA was a reasonable palliative treatment option with limited toxicity for these end-stage mCRPC patients with visceral metastasis with adequate PSA stabilization. A synergistic drug amalgamation may be an ideal way to boost the outcome in the future.
REF00147	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Incresae of serum troponin I levels	0.04 ng/ml	ng/ml	.	.	.	Patients with prostate cancer and neuroendocrine tumours referred for PRRT and RLT.	.	.	.	.	.	.	.	"In all patients, the value of troponin I was in normal range. In all patients, the median values of serum troponin I before and after treatment were 0.2 &plusmn; 0.02 (range: 0.00-0.42) and 0.28 &plusmn; 0.02 (range: 0.00-0.46) ng/ml, respectively (p > 0.05). In the prostate cancer patients, the median values of serum troponin I before and after treatment were 0.26 &plusmn; 0.04 (0.04-0.42) and 0.30 &plusmn; 0.04 (0.00-0.41) ng/ml, respectively (p > 0.05). In the NET patients, the median values of serum troponin I before and after treatment were 0.18 &plusmn; 0.03 (0.00-0.42) and 0.17 &plusmn; 0.03 (0.00-0.46) ng/ml, respectively (p > 0.05)."	.
REF00147	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Serum troponin I decrease rate	0.01 ng/ml	ng/ml	.	.	.	Patients with prostate cancer and neuroendocrine tumours referred for PRRT and RLT.	.	.	.	.	.	.	.	"In all patients, the value of troponin I was in normal range. In all patients, the median values of serum troponin I before and after treatment were 0.2 &plusmn; 0.02 (range: 0.00-0.42) and 0.28 &plusmn; 0.02 (range: 0.00-0.46) ng/ml, respectively (p > 0.05). In the prostate cancer patients, the median values of serum troponin I before and after treatment were 0.26 &plusmn; 0.04 (0.04-0.42) and 0.30 &plusmn; 0.04 (0.00-0.41) ng/ml, respectively (p > 0.05). In the NET patients, the median values of serum troponin I before and after treatment were 0.18 &plusmn; 0.03 (0.00-0.42) and 0.17 &plusmn; 0.03 (0.00-0.46) ng/ml, respectively (p > 0.05)."	.
REF00148	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Flare reaction rate	42%	%	.	.	.	12 GEP neuroendocrine tumours patients.	.	.	.	.	.	.	.	"In our first 12 patients who received Lutetium Lu-177 dotatate, tumor flare reactions occurred in 5 patients due to worsening symptoms of bone or soft tissue metastasis. This flare reaction can be mitigated with short course of corticosteroid therapy or other strategies."	.
REF00151	PDC_00027	SDHB positive metastatic paraganglioma	A 29-year-old male with SDHB positive metastatic paraganglioma.	Identified from the Human Clinical Data	High Expreesion	Thyroid stimulating hormone levels	73.04 &micro;IU/ml	&micro;IU/ml	NCT03206060	"Background:Pheochromocytoma and paraganglioma are rare tumors. They usually form inside and near the adrenal gland or in the neck region. Not all these tumors can be removed with surgery, and there are no good treatments if the disease has spread. Researchers think a new drug may be able to help.Objective:To learn the safety and tolerability of Lu-177-DOTATATE. Also, to see if it improves the length of time it takes for the cancer to return.Eligibility:Adults who have an inoperable tumor of the study cancer that can be detected with Ga-68-DOTATATE PET/CT imagingDesign:Participants will be screened with a medical history, physical exam, and blood tests.Eligible participants will be admitted to the NIH Clinical Center.Participants will get the study drug in an intravenous infusion. They will get 4 doses, given about 8 weeks apart.Between 4 and 24 hours after each study drug dose, participants will have scans taken. They will lie on their back on a scanner table.Participants will have vital signs taken. They will give blood and urine samples.During the study, participants will have other scans taken. Some scans will use a radioactive tracer.Participants will complete quality of life questionnaires.Participants will be contacted by phone 1-3 days after they leave the Clinical Center. They will then be followed every 3 to 6 months for 3 years or until their disease gets worse."	Phase 2	.	.	.	.	.	1 month	200mCi	.	"The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi <sup>177</sup>Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 &mu;IU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to <sup>177</sup>Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of <sup>177</sup>Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved."	.
REF00151	PDC_00027	SDHB positive metastatic paraganglioma	A 29-year-old male with SDHB positive metastatic paraganglioma.	Identified from the Human Clinical Data	High Expreesion	Free thyroxine level	0.3 ng/dl	ng/dl	NCT03206060	"Background:Pheochromocytoma and paraganglioma are rare tumors. They usually form inside and near the adrenal gland or in the neck region. Not all these tumors can be removed with surgery, and there are no good treatments if the disease has spread. Researchers think a new drug may be able to help.Objective:To learn the safety and tolerability of Lu-177-DOTATATE. Also, to see if it improves the length of time it takes for the cancer to return.Eligibility:Adults who have an inoperable tumor of the study cancer that can be detected with Ga-68-DOTATATE PET/CT imagingDesign:Participants will be screened with a medical history, physical exam, and blood tests.Eligible participants will be admitted to the NIH Clinical Center.Participants will get the study drug in an intravenous infusion. They will get 4 doses, given about 8 weeks apart.Between 4 and 24 hours after each study drug dose, participants will have scans taken. They will lie on their back on a scanner table.Participants will have vital signs taken. They will give blood and urine samples.During the study, participants will have other scans taken. Some scans will use a radioactive tracer.Participants will complete quality of life questionnaires.Participants will be contacted by phone 1-3 days after they leave the Clinical Center. They will then be followed every 3 to 6 months for 3 years or until their disease gets worse."	Phase 2	.	.	.	.	.	1 month	200mCi	Immunoassay	"The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi <sup>177</sup>Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 &mu;IU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to <sup>177</sup>Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of <sup>177</sup>Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved."	.
REF00151	PDC_00027	SDHB positive metastatic paraganglioma	A 29-year-old male with SDHB positive metastatic paraganglioma.	Identified from the Human Clinical Data	High Expreesion	TSH receptor antibody level	1 IU/L	IU/L	NCT03206060	"Background:Pheochromocytoma and paraganglioma are rare tumors. They usually form inside and near the adrenal gland or in the neck region. Not all these tumors can be removed with surgery, and there are no good treatments if the disease has spread. Researchers think a new drug may be able to help.Objective:To learn the safety and tolerability of Lu-177-DOTATATE. Also, to see if it improves the length of time it takes for the cancer to return.Eligibility:Adults who have an inoperable tumor of the study cancer that can be detected with Ga-68-DOTATATE PET/CT imagingDesign:Participants will be screened with a medical history, physical exam, and blood tests.Eligible participants will be admitted to the NIH Clinical Center.Participants will get the study drug in an intravenous infusion. They will get 4 doses, given about 8 weeks apart.Between 4 and 24 hours after each study drug dose, participants will have scans taken. They will lie on their back on a scanner table.Participants will have vital signs taken. They will give blood and urine samples.During the study, participants will have other scans taken. Some scans will use a radioactive tracer.Participants will complete quality of life questionnaires.Participants will be contacted by phone 1-3 days after they leave the Clinical Center. They will then be followed every 3 to 6 months for 3 years or until their disease gets worse."	Phase 2	.	.	.	.	.	1 month	200mCi	Immunoassay	"The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi <sup>177</sup>Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 &mu;IU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to <sup>177</sup>Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of <sup>177</sup>Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved."	.
REF00151	PDC_00027	SDHB positive metastatic paraganglioma	A 29-year-old male with SDHB positive metastatic paraganglioma.	Identified from the Human Clinical Data	High Expreesion	Thyroid stimulating index	1.3	.	NCT03206060	"Background:Pheochromocytoma and paraganglioma are rare tumors. They usually form inside and near the adrenal gland or in the neck region. Not all these tumors can be removed with surgery, and there are no good treatments if the disease has spread. Researchers think a new drug may be able to help.Objective:To learn the safety and tolerability of Lu-177-DOTATATE. Also, to see if it improves the length of time it takes for the cancer to return.Eligibility:Adults who have an inoperable tumor of the study cancer that can be detected with Ga-68-DOTATATE PET/CT imagingDesign:Participants will be screened with a medical history, physical exam, and blood tests.Eligible participants will be admitted to the NIH Clinical Center.Participants will get the study drug in an intravenous infusion. They will get 4 doses, given about 8 weeks apart.Between 4 and 24 hours after each study drug dose, participants will have scans taken. They will lie on their back on a scanner table.Participants will have vital signs taken. They will give blood and urine samples.During the study, participants will have other scans taken. Some scans will use a radioactive tracer.Participants will complete quality of life questionnaires.Participants will be contacted by phone 1-3 days after they leave the Clinical Center. They will then be followed every 3 to 6 months for 3 years or until their disease gets worse."	Phase 2	.	.	.	.	.	1 month	200mCi	.	"The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi <sup>177</sup>Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 &mu;IU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to <sup>177</sup>Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of <sup>177</sup>Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved."	.
REF00151	PDC_00027	SDHB positive metastatic paraganglioma	A 29-year-old male with SDHB positive metastatic paraganglioma.	Identified from the Human Clinical Data	High Expreesion	Anti-thyroid peroxidase antibody level	"1,000 IU/ml"	IU/ml	NCT03206060	"Background:Pheochromocytoma and paraganglioma are rare tumors. They usually form inside and near the adrenal gland or in the neck region. Not all these tumors can be removed with surgery, and there are no good treatments if the disease has spread. Researchers think a new drug may be able to help.Objective:To learn the safety and tolerability of Lu-177-DOTATATE. Also, to see if it improves the length of time it takes for the cancer to return.Eligibility:Adults who have an inoperable tumor of the study cancer that can be detected with Ga-68-DOTATATE PET/CT imagingDesign:Participants will be screened with a medical history, physical exam, and blood tests.Eligible participants will be admitted to the NIH Clinical Center.Participants will get the study drug in an intravenous infusion. They will get 4 doses, given about 8 weeks apart.Between 4 and 24 hours after each study drug dose, participants will have scans taken. They will lie on their back on a scanner table.Participants will have vital signs taken. They will give blood and urine samples.During the study, participants will have other scans taken. Some scans will use a radioactive tracer.Participants will complete quality of life questionnaires.Participants will be contacted by phone 1-3 days after they leave the Clinical Center. They will then be followed every 3 to 6 months for 3 years or until their disease gets worse."	Phase 2	.	.	.	.	.	1 month	200mCi	.	"The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi <sup>177</sup>Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 &mu;IU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to <sup>177</sup>Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of <sup>177</sup>Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved."	.
REF00151	PDC_00027	SDHB positive metastatic paraganglioma	A 29-year-old male with SDHB positive metastatic paraganglioma.	Identified from the Human Clinical Data	High Expreesion	Anti-thyroglobulin antibody level	668 IU/ml	IU/ml	NCT03206060	"Background:Pheochromocytoma and paraganglioma are rare tumors. They usually form inside and near the adrenal gland or in the neck region. Not all these tumors can be removed with surgery, and there are no good treatments if the disease has spread. Researchers think a new drug may be able to help.Objective:To learn the safety and tolerability of Lu-177-DOTATATE. Also, to see if it improves the length of time it takes for the cancer to return.Eligibility:Adults who have an inoperable tumor of the study cancer that can be detected with Ga-68-DOTATATE PET/CT imagingDesign:Participants will be screened with a medical history, physical exam, and blood tests.Eligible participants will be admitted to the NIH Clinical Center.Participants will get the study drug in an intravenous infusion. They will get 4 doses, given about 8 weeks apart.Between 4 and 24 hours after each study drug dose, participants will have scans taken. They will lie on their back on a scanner table.Participants will have vital signs taken. They will give blood and urine samples.During the study, participants will have other scans taken. Some scans will use a radioactive tracer.Participants will complete quality of life questionnaires.Participants will be contacted by phone 1-3 days after they leave the Clinical Center. They will then be followed every 3 to 6 months for 3 years or until their disease gets worse."	Phase 2	.	.	.	.	.	1 month	200mCi	.	"The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi <sup>177</sup>Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 &mu;IU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to <sup>177</sup>Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of <sup>177</sup>Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved."	.
REF00151	PDC_00027	SDHB positive metastatic paraganglioma	A 29-year-old male with SDHB positive metastatic paraganglioma.	Identified from the Human Clinical Data	High Expreesion	Total triiodothyronine	54 ng/dl	ng/dl	NCT03206060	"Background:Pheochromocytoma and paraganglioma are rare tumors. They usually form inside and near the adrenal gland or in the neck region. Not all these tumors can be removed with surgery, and there are no good treatments if the disease has spread. Researchers think a new drug may be able to help.Objective:To learn the safety and tolerability of Lu-177-DOTATATE. Also, to see if it improves the length of time it takes for the cancer to return.Eligibility:Adults who have an inoperable tumor of the study cancer that can be detected with Ga-68-DOTATATE PET/CT imagingDesign:Participants will be screened with a medical history, physical exam, and blood tests.Eligible participants will be admitted to the NIH Clinical Center.Participants will get the study drug in an intravenous infusion. They will get 4 doses, given about 8 weeks apart.Between 4 and 24 hours after each study drug dose, participants will have scans taken. They will lie on their back on a scanner table.Participants will have vital signs taken. They will give blood and urine samples.During the study, participants will have other scans taken. Some scans will use a radioactive tracer.Participants will complete quality of life questionnaires.Participants will be contacted by phone 1-3 days after they leave the Clinical Center. They will then be followed every 3 to 6 months for 3 years or until their disease gets worse."	Phase 2	.	.	.	.	.	1 month	200mCi	Mass spectrometry assay	"The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi <sup>177</sup>Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 &mu;IU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to <sup>177</sup>Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of <sup>177</sup>Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved."	.
REF00151	PDC_00027	SDHB positive metastatic paraganglioma	A 29-year-old male with SDHB positive metastatic paraganglioma.	Identified from the Human Clinical Data	High Expreesion	TSH receptor antibody level	1.75 IU/L	IU/L	NCT03206060	"Background:Pheochromocytoma and paraganglioma are rare tumors. They usually form inside and near the adrenal gland or in the neck region. Not all these tumors can be removed with surgery, and there are no good treatments if the disease has spread. Researchers think a new drug may be able to help.Objective:To learn the safety and tolerability of Lu-177-DOTATATE. Also, to see if it improves the length of time it takes for the cancer to return.Eligibility:Adults who have an inoperable tumor of the study cancer that can be detected with Ga-68-DOTATATE PET/CT imagingDesign:Participants will be screened with a medical history, physical exam, and blood tests.Eligible participants will be admitted to the NIH Clinical Center.Participants will get the study drug in an intravenous infusion. They will get 4 doses, given about 8 weeks apart.Between 4 and 24 hours after each study drug dose, participants will have scans taken. They will lie on their back on a scanner table.Participants will have vital signs taken. They will give blood and urine samples.During the study, participants will have other scans taken. Some scans will use a radioactive tracer.Participants will complete quality of life questionnaires.Participants will be contacted by phone 1-3 days after they leave the Clinical Center. They will then be followed every 3 to 6 months for 3 years or until their disease gets worse."	Phase 2	.	.	.	.	.	1 month	200mCi	.	"The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi <sup>177</sup>Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 &mu;IU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to <sup>177</sup>Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of <sup>177</sup>Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	12.80%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	38.30%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	25.50%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	23.40%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	4.30%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	34.00%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	10.60%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	51.10%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	2.10%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	23.40%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	31.90%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	42.60%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	0%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	4.30%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	51.10%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	44.70%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression rate	59.60%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Death rate	44.70%	%	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	10 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	68Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00152	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	15 months	months	.	.	.	Patients with metastatic castration-resistant prostate cancer who underwent 68Ga-PSMA and FDG PET-CT scans.	.	.	.	.	.	.	6AN2237:AN22568Ga-PSMA/18F-FDG PET-CT assay	"In the period between 2016 and 2018, 58 patients were referred for [<sup>177</sup>Lu]-PSMA PRLT to the center, of which 51 patients underwent both [68Ga]-PSMA and FDG PET-CT scans and provisionally qualified for the analysis; out of these complete information of four patients was not available and hence were excluded. Thus, 47 patients were retrospectively recruited and categorized according to the proposed Pro-PET scoring scheme and were analyzed as discussed above. The cohort comprised of heavily pretreated patients with 2 (4.3%) underwent radical prostatectomy; surgical castration was performed in 45 (95.7%) patients; first-line hormonal therapy (with estrogen analogues, leutinizing hormone releasing hormone agonists and antagonists and antiandrogens) in 44 (93.6%) patients, second-line hormonal therapy (with CYP17 blockers and newer anti-androgens) in 34 (72.4%) patients; first-line chemotherapy (with docetaxel) in 33 (70.2%) patients, second-line chemotherapy (with cabazitaxel, oral metronomic chemotherapy, etc.) in 22 (46.8%) and radiotherapy in 26 (55.3%) patients."	.
REF00154	PDC_00027	SDHB positive metastatic paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	30%	%	.	.	.	37 patients affected by neuroendocrine tumors.	.	.	.	.	Five cycles of 5.5 gbq each every 8 weeks	Cumulative activity of 27.5 GBq	.	"Thirty-three of 37 patients were evaluable for response. Objective responses included partial response (PR) in 10 patients (30%), stable disease (SD) in 18 patients (55%), with a DCR of 85%. Median follow up was 38 months (range 4.6-51.1 months). Median PFS was 31.4 months (17.6-45.4) and mOS was not reached."	.
REF00154	PDC_00027	SDHB positive metastatic paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	55%	%	.	.	.	37 patients affected by neuroendocrine tumors.	.	.	.	.	Five cycles of 5.5 gbq each every 8 weeks	Cumulative activity of 27.5 GBq	.	"Thirty-three of 37 patients were evaluable for response. Objective responses included partial response (PR) in 10 patients (30%), stable disease (SD) in 18 patients (55%), with a DCR of 85%. Median follow up was 38 months (range 4.6-51.1 months). Median PFS was 31.4 months (17.6-45.4) and mOS was not reached."	.
REF00154	PDC_00027	SDHB positive metastatic paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	85%	%	.	.	.	37 patients affected by neuroendocrine tumors.	.	.	.	.	Five cycles of 5.5 gbq each every 8 weeks	Cumulative activity of 27.5 GBq	.	"Thirty-three of 37 patients were evaluable for response. Objective responses included partial response (PR) in 10 patients (30%), stable disease (SD) in 18 patients (55%), with a DCR of 85%. Median follow up was 38 months (range 4.6-51.1 months). Median PFS was 31.4 months (17.6-45.4) and mOS was not reached."	.
REF00154	PDC_00027	SDHB positive metastatic paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Median follow-up	38 months	months	.	.	.	37 patients affected by neuroendocrine tumors.	.	.	.	.	Five cycles of 5.5 gbq each every 8 weeks	Cumulative activity of 27.5 GBq	.	"Thirty-three of 37 patients were evaluable for response. Objective responses included partial response (PR) in 10 patients (30%), stable disease (SD) in 18 patients (55%), with a DCR of 85%. Median follow up was 38 months (range 4.6-51.1 months). Median PFS was 31.4 months (17.6-45.4) and mOS was not reached."	.
REF00154	PDC_00027	SDHB positive metastatic paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	31.4 months	months	.	.	.	37 patients affected by neuroendocrine tumors.	.	.	.	.	Five cycles of 5.5 gbq each every 8 weeks	Cumulative activity of 27.5 GBq	.	"Thirty-three of 37 patients were evaluable for response. Objective responses included partial response (PR) in 10 patients (30%), stable disease (SD) in 18 patients (55%), with a DCR of 85%. Median follow up was 38 months (range 4.6-51.1 months). Median PFS was 31.4 months (17.6-45.4) and mOS was not reached."	.
REF00155	PDC_00027	Progressive well-differentiated neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	16.92 months	months	.	.	.	"122 patients with progressive well-differentiated neuroendocrine tumour (small intestinal, pancreatic, colon, gastric, lung, thymic and unknown primaries)."	.	.	.	.	3-4 doses of prrt	7.4/3.7 GBq	.	"Among patients who received 3-4 doses of PRRT, patients with a CS &le; 4 experienced a median PFS of not reached (NR) (95% CI 18 - NR) while patients with a CS > 4 experienced a median PFS of 16.92 months (95% CI 13.21 - NR). Among patients who received zero doses of PRRT, patients with a CS &le; 4 experienced a median PFS of 9.82 months (95% CI 5.78 - 18.6) while patients with a CS > 4 experienced a median PFS of 9.35 months (95% CI 2.43 - 18.1). Among patients who received 1-2 doses of PRRT, patients with a CS &le; 4 experienced a median PFS of 6.83 months (95% CI NR - NR) while patients with a CS > 4 experienced a median PFS of 3.06 months (95% CI.49 - 8.51) (Log rank-test p <.0001)."	.
REF00155	PDC_00027	Progressive well-differentiated neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	9.82 months	months	.	.	.	"122 patients with progressive well-differentiated neuroendocrine tumour (small intestinal, pancreatic, colon, gastric, lung, thymic and unknown primaries)."	.	.	.	.	Zero doses of prrt	7.4 /3.7 GBq ( GBq)	.	"Among patients who received 3-4 doses of PRRT, patients with a CS &le; 4 experienced a median PFS of not reached (NR) (95% CI 18 - NR) while patients with a CS > 4 experienced a median PFS of 16.92 months (95% CI 13.21 - NR). Among patients who received zero doses of PRRT, patients with a CS &le; 4 experienced a median PFS of 9.82 months (95% CI 5.78 - 18.6) while patients with a CS > 4 experienced a median PFS of 9.35 months (95% CI 2.43 - 18.1). Among patients who received 1-2 doses of PRRT, patients with a CS &le; 4 experienced a median PFS of 6.83 months (95% CI NR - NR) while patients with a CS > 4 experienced a median PFS of 3.06 months (95% CI.49 - 8.51) (Log rank-test p <.0001)."	.
REF00155	PDC_00027	Progressive well-differentiated neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	9.35 months	months	.	.	.	"122 patients with progressive well-differentiated neuroendocrine tumour (small intestinal, pancreatic, colon, gastric, lung, thymic and unknown primaries)."	.	.	.	.	Zero doses of prrt	7.4 /3.7 GBq ( GBq)	.	"Among patients who received 3-4 doses of PRRT, patients with a CS &le; 4 experienced a median PFS of not reached (NR) (95% CI 18 - NR) while patients with a CS > 4 experienced a median PFS of 16.92 months (95% CI 13.21 - NR). Among patients who received zero doses of PRRT, patients with a CS &le; 4 experienced a median PFS of 9.82 months (95% CI 5.78 - 18.6) while patients with a CS > 4 experienced a median PFS of 9.35 months (95% CI 2.43 - 18.1). Among patients who received 1-2 doses of PRRT, patients with a CS &le; 4 experienced a median PFS of 6.83 months (95% CI NR - NR) while patients with a CS > 4 experienced a median PFS of 3.06 months (95% CI.49 - 8.51) (Log rank-test p <.0001)."	.
REF00155	PDC_00027	Progressive well-differentiated neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	6.83 months	months	.	.	.	"122 patients with progressive well-differentiated neuroendocrine tumour (small intestinal, pancreatic, colon, gastric, lung, thymic and unknown primaries)."	.	.	.	.	1-2 doses of prrt	7.4/3.7 GBq	.	"Among patients who received 3-4 doses of PRRT, patients with a CS &le; 4 experienced a median PFS of not reached (NR) (95% CI 18 - NR) while patients with a CS > 4 experienced a median PFS of 16.92 months (95% CI 13.21 - NR). Among patients who received zero doses of PRRT, patients with a CS &le; 4 experienced a median PFS of 9.82 months (95% CI 5.78 - 18.6) while patients with a CS > 4 experienced a median PFS of 9.35 months (95% CI 2.43 - 18.1). Among patients who received 1-2 doses of PRRT, patients with a CS &le; 4 experienced a median PFS of 6.83 months (95% CI NR - NR) while patients with a CS > 4 experienced a median PFS of 3.06 months (95% CI.49 - 8.51) (Log rank-test p <.0001)."	.
REF00155	PDC_00027	Progressive well-differentiated neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	3.06 months	months	.	.	.	"122 patients with progressive well-differentiated neuroendocrine tumour (small intestinal, pancreatic, colon, gastric, lung, thymic and unknown primaries)."	.	.	.	.	1-2 doses of prrt	7.4/3.7 GBq	.	"Among patients who received 3-4 doses of PRRT, patients with a CS &le; 4 experienced a median PFS of not reached (NR) (95% CI 18 - NR) while patients with a CS > 4 experienced a median PFS of 16.92 months (95% CI 13.21 - NR). Among patients who received zero doses of PRRT, patients with a CS &le; 4 experienced a median PFS of 9.82 months (95% CI 5.78 - 18.6) while patients with a CS > 4 experienced a median PFS of 9.35 months (95% CI 2.43 - 18.1). Among patients who received 1-2 doses of PRRT, patients with a CS &le; 4 experienced a median PFS of 6.83 months (95% CI NR - NR) while patients with a CS > 4 experienced a median PFS of 3.06 months (95% CI.49 - 8.51) (Log rank-test p <.0001)."	.
REF00156	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	A 68-year-old man diagnosed with adenocarcinoma prostate (Gleason score 5 + 5).	Identified from the Human Clinical Data	High Expreesion	PSA decline	17.8 ng/mL	ng/mL	.	.	.	.	.	.	.	.	2 cycles doses at intervals of 12 weeks	6 GBq	68Ga-PSMA PET-CT assay	He received 2 cycles of 6 GBq doses of <sup>177</sup>Lu-PSMA-617 at intervals of 12 weeks along with daily 160 mg of oral enzalutamide. His PSA level declined from 20 ng/mL at baseline to 2.2 ng/mL (89% reduction from baseline) after completion of 2 cycles of <sup>177</sup>Lu-PSMA-617 with concomitant oral enzalutamide.	.
REF00156	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	A 68-year-old man diagnosed with adenocarcinoma prostate (Gleason score 5 + 5).	Identified from the Human Clinical Data	High Expreesion	PSA decline rate	89%	%	.	.	.	.	.	.	.	.	2 cycles doses at intervals of 12 weeks	6 GBq	68Ga-PSMA PET-CT assay	He received 2 cycles of 6 GBq doses of <sup>177</sup>Lu-PSMA-617 at intervals of 12 weeks along with daily 160 mg of oral enzalutamide. His PSA level declined from 20 ng/mL at baseline to 2.2 ng/mL (89% reduction from baseline) after completion of 2 cycles of <sup>177</sup>Lu-PSMA-617 with concomitant oral enzalutamide.	.
REF00158	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Rate of PSA <0.2 ng/mL	25%	%	NCT04343885	This phase 2 randomised clinical trial will compare the effectiveness of Lu-PSMA therapy followed by docetaxel chemotherapy versus docetaxel chemotherapy on its own in patients with newly-diagnosed high-volume metastatic hormone-naive prostate cancer (mHNPC).	Phase 2	140 patients wit high-volume metastatic hormone-naive prostate cancer.	.	.	.	.	2 cycles	7.5 GBq	.	"The primary endpoint of this study is undetectable PSA (PSA &le;0.2 ng/mL) at 12 months after initiation of protocol therapy. In the CHAARTED study, 27% of all mHNPC patients treated with ADT+ docetaxel attained a PSA &le;0.2 ng/mL at 12 months. We have assumed that 25% of patients in the control arm (Arm B) will have PSA &le;0.2 ng/mL at 12 months. With 140 patients randomized 1:1 between the treatment arms, the study will have 85% power to reject the null hypothesis that the 12-month undetectable PSA rate is the same between the arms if the true 12-month undetectable PSA rate in the experimental arm (Arm A) is 50%. "	.
REF00159	PDC_00027	Atypical and anaplastic meningiomas	A 62-year-old man presented with a history of atypical meningioma (World Health Organization grade II) and recurrent as anaplastic meningioma (World Health Organization grade III).	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	7%	%	.	.	.	.	.	.	.	.	.	7.4 GBq (200 mCi)	111In-octreotide scan assay	"A transient increase in tumor volume was observed after the first cycle, which may have represented delayed treatment effect or pseudoprogression secondary to vasogenic edema. Subsequently, the tumor volume decreased by 7% and remained stable with minimal change in volume throughout the remainder of treatment. Over the 4 cycles (8 months) of treatment, the tumor volume increased only 16% during <sup>177</sup>Lu-dotatate therapy in comparison to the rapid increase of 169% during the 8 months prior to <sup>177</sup>Lu-dotatate initiation. However, the tumor resumed its previous rapid growth after therapy cessation."	.
REF00160	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	64.00%	%	.	.	.	50 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	Median 7.4 GBq	.	.	"PSMA TRT involves conjugating radionuclides to antibodies and small molecule-ligands directed against PSMA. The most common radionuclide utilized to date is Lutetium-177, a beta-emitter with a mean path-length of 0.7 mm and maximum of 1.8 mm. Gamma-ray emission allows for concurrent single photon emission computed tomography (SPECT). Actinium-225 has been the most common alpha-emitter utilized. Alpha-emitters are thousands of times more potent and can induce double-stranded DNA breaks more difficult to repair, but mean path-length is much shorter than beta-emitters (under 0.01 mm)."
REF00160	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	36.00%	%	.	.	.	14 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	Mean 7.0 GBq	.	.	"PSMA TRT involves conjugating radionuclides to antibodies and small molecule-ligands directed against PSMA. The most common radionuclide utilized to date is Lutetium-177, a beta-emitter with a mean path-length of 0.7 mm and maximum of 1.8 mm. Gamma-ray emission allows for concurrent single photon emission computed tomography (SPECT). Actinium-225 has been the most common alpha-emitter utilized. Alpha-emitters are thousands of times more potent and can induce double-stranded DNA breaks more difficult to repair, but mean path-length is much shorter than beta-emitters (under 0.01 mm)."
REF00160	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	61.00%	%	.	.	.	44 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 cycle	7.4-22.2 GBq x 2	.	.	"PSMA TRT involves conjugating radionuclides to antibodies and small molecule-ligands directed against PSMA. The most common radionuclide utilized to date is Lutetium-177, a beta-emitter with a mean path-length of 0.7 mm and maximum of 1.8 mm. Gamma-ray emission allows for concurrent single photon emission computed tomography (SPECT). Actinium-225 has been the most common alpha-emitter utilized. Alpha-emitters are thousands of times more potent and can induce double-stranded DNA breaks more difficult to repair, but mean path-length is much shorter than beta-emitters (under 0.01 mm)."
REF00160	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	38.00%	%	.	.	.	64 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	6.0/7.4 GBq	.	.	"PSMA TRT involves conjugating radionuclides to antibodies and small molecule-ligands directed against PSMA. The most common radionuclide utilized to date is Lutetium-177, a beta-emitter with a mean path-length of 0.7 mm and maximum of 1.8 mm. Gamma-ray emission allows for concurrent single photon emission computed tomography (SPECT). Actinium-225 has been the most common alpha-emitter utilized. Alpha-emitters are thousands of times more potent and can induce double-stranded DNA breaks more difficult to repair, but mean path-length is much shorter than beta-emitters (under 0.01 mm)."
REF00160	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	66.00%	%	.	.	.	200 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6 cycles	6-8 GBq	.	.	"PSMA TRT involves conjugating radionuclides to antibodies and small molecule-ligands directed against PSMA. The most common radionuclide utilized to date is Lutetium-177, a beta-emitter with a mean path-length of 0.7 mm and maximum of 1.8 mm. Gamma-ray emission allows for concurrent single photon emission computed tomography (SPECT). Actinium-225 has been the most common alpha-emitter utilized. Alpha-emitters are thousands of times more potent and can induce double-stranded DNA breaks more difficult to repair, but mean path-length is much shorter than beta-emitters (under 0.01 mm)."
REF00160	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median PSA	189.8 ng/mL	ng/mL	.	.	.	50 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	Median 7.4 GBq	.	.	"PSMA TRT involves conjugating radionuclides to antibodies and small molecule-ligands directed against PSMA. The most common radionuclide utilized to date is Lutetium-177, a beta-emitter with a mean path-length of 0.7 mm and maximum of 1.8 mm. Gamma-ray emission allows for concurrent single photon emission computed tomography (SPECT). Actinium-225 has been the most common alpha-emitter utilized. Alpha-emitters are thousands of times more potent and can induce double-stranded DNA breaks more difficult to repair, but mean path-length is much shorter than beta-emitters (under 0.01 mm)."
REF00160	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median PSA	88 ng/mL	ng/mL	.	.	.	14 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	Mean 7.0 GBq	.	.	"PSMA TRT involves conjugating radionuclides to antibodies and small molecule-ligands directed against PSMA. The most common radionuclide utilized to date is Lutetium-177, a beta-emitter with a mean path-length of 0.7 mm and maximum of 1.8 mm. Gamma-ray emission allows for concurrent single photon emission computed tomography (SPECT). Actinium-225 has been the most common alpha-emitter utilized. Alpha-emitters are thousands of times more potent and can induce double-stranded DNA breaks more difficult to repair, but mean path-length is much shorter than beta-emitters (under 0.01 mm)."
REF00160	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median PSA	182.97 ng/mL	ng/mL	.	.	.	44 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 cycle	7.4-22.2 GBq x 2	.	.	"PSMA TRT involves conjugating radionuclides to antibodies and small molecule-ligands directed against PSMA. The most common radionuclide utilized to date is Lutetium-177, a beta-emitter with a mean path-length of 0.7 mm and maximum of 1.8 mm. Gamma-ray emission allows for concurrent single photon emission computed tomography (SPECT). Actinium-225 has been the most common alpha-emitter utilized. Alpha-emitters are thousands of times more potent and can induce double-stranded DNA breaks more difficult to repair, but mean path-length is much shorter than beta-emitters (under 0.01 mm)."
REF00160	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median PSA	75 ng/mL	ng/mL	.	.	.	64 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	6.0/7.4 GBq	.	.	"PSMA TRT involves conjugating radionuclides to antibodies and small molecule-ligands directed against PSMA. The most common radionuclide utilized to date is Lutetium-177, a beta-emitter with a mean path-length of 0.7 mm and maximum of 1.8 mm. Gamma-ray emission allows for concurrent single photon emission computed tomography (SPECT). Actinium-225 has been the most common alpha-emitter utilized. Alpha-emitters are thousands of times more potent and can induce double-stranded DNA breaks more difficult to repair, but mean path-length is much shorter than beta-emitters (under 0.01 mm)."
REF00160	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	13.3 months	months	.	.	.	50 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	Median 7.4 GBq	.	.	"PSMA TRT involves conjugating radionuclides to antibodies and small molecule-ligands directed against PSMA. The most common radionuclide utilized to date is Lutetium-177, a beta-emitter with a mean path-length of 0.7 mm and maximum of 1.8 mm. Gamma-ray emission allows for concurrent single photon emission computed tomography (SPECT). Actinium-225 has been the most common alpha-emitter utilized. Alpha-emitters are thousands of times more potent and can induce double-stranded DNA breaks more difficult to repair, but mean path-length is much shorter than beta-emitters (under 0.01 mm)."
REF00160	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	50 weeks	weeks	.	.	.	14 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	Mean 7.0 GBq	.	.	"PSMA TRT involves conjugating radionuclides to antibodies and small molecule-ligands directed against PSMA. The most common radionuclide utilized to date is Lutetium-177, a beta-emitter with a mean path-length of 0.7 mm and maximum of 1.8 mm. Gamma-ray emission allows for concurrent single photon emission computed tomography (SPECT). Actinium-225 has been the most common alpha-emitter utilized. Alpha-emitters are thousands of times more potent and can induce double-stranded DNA breaks more difficult to repair, but mean path-length is much shorter than beta-emitters (under 0.01 mm)."
REF00160	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	16 months	months	.	.	.	44 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 cycle	7.4-22.2 GBq x 2	.	.	"PSMA TRT involves conjugating radionuclides to antibodies and small molecule-ligands directed against PSMA. The most common radionuclide utilized to date is Lutetium-177, a beta-emitter with a mean path-length of 0.7 mm and maximum of 1.8 mm. Gamma-ray emission allows for concurrent single photon emission computed tomography (SPECT). Actinium-225 has been the most common alpha-emitter utilized. Alpha-emitters are thousands of times more potent and can induce double-stranded DNA breaks more difficult to repair, but mean path-length is much shorter than beta-emitters (under 0.01 mm)."
REF00160	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	6.9 months	months	.	.	.	50 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	Median 7.4 GBq	.	.	"PSMA TRT involves conjugating radionuclides to antibodies and small molecule-ligands directed against PSMA. The most common radionuclide utilized to date is Lutetium-177, a beta-emitter with a mean path-length of 0.7 mm and maximum of 1.8 mm. Gamma-ray emission allows for concurrent single photon emission computed tomography (SPECT). Actinium-225 has been the most common alpha-emitter utilized. Alpha-emitters are thousands of times more potent and can induce double-stranded DNA breaks more difficult to repair, but mean path-length is much shorter than beta-emitters (under 0.01 mm)."
REF00162	PDC_00027	High-grade gliomas 	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	12.50%	%	.	.	.	16 patients with high-grade gliomas (10 males and 6 females).	.	.	.	.	1 to 4 cycles	"3.7 to 29.6 GBq (median, 10.45 GBq)"	MRI assay	"In total, 16 subjects (10 males and 6 females) with a mean age of 55.68 &plusmn; 13.17 years (26-73 years) participated in the study. Of them, 8 patients were new HGG cases, and 8 patients had recurrent tumors. The participants' responses to treatments were complete remission in 12.5% of (n = 2), partial remission in 31.25% (n = 5), disease stability in 18.7% (n = 3), and disease progression in 37.5% (n = 6). In total, pretreatment and posttreatment Karnofsky Performance Score and Eastern Cooperative Oncology Group scores did not improved (P > 0.05). The patients were followed up from 1 month to 26 months (median, 3 months)."	.
REF00162	PDC_00027	High-grade gliomas 	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	31.25%	%	.	.	.	16 patients with high-grade gliomas (10 males and 6 females).	.	.	.	.	1 to 4 cycles	"3.7 to 29.6 GBq (median, 10.45 GBq)"	MRI assay	"In total, 16 subjects (10 males and 6 females) with a mean age of 55.68 &plusmn; 13.17 years (26-73 years) participated in the study. Of them, 8 patients were new HGG cases, and 8 patients had recurrent tumors. The participants' responses to treatments were complete remission in 12.5% of (n = 2), partial remission in 31.25% (n = 5), disease stability in 18.7% (n = 3), and disease progression in 37.5% (n = 6). In total, pretreatment and posttreatment Karnofsky Performance Score and Eastern Cooperative Oncology Group scores did not improved (P > 0.05). The patients were followed up from 1 month to 26 months (median, 3 months)."	.
REF00162	PDC_00027	High-grade gliomas 	.	Identified from the Human Clinical Data	High Expreesion	Disease stable rate	18.70%	%	.	.	.	16 patients with high-grade gliomas (10 males and 6 females).	.	.	.	.	1 to 4 cycles	"3.7 to 29.6 GBq (median, 10.45 GBq)"	MRI assay	"In total, 16 subjects (10 males and 6 females) with a mean age of 55.68 &plusmn; 13.17 years (26-73 years) participated in the study. Of them, 8 patients were new HGG cases, and 8 patients had recurrent tumors. The participants' responses to treatments were complete remission in 12.5% of (n = 2), partial remission in 31.25% (n = 5), disease stability in 18.7% (n = 3), and disease progression in 37.5% (n = 6). In total, pretreatment and posttreatment Karnofsky Performance Score and Eastern Cooperative Oncology Group scores did not improved (P > 0.05). The patients were followed up from 1 month to 26 months (median, 3 months)."	.
REF00162	PDC_00027	High-grade gliomas 	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	37.50%	%	.	.	.	16 patients with high-grade gliomas (10 males and 6 females).	.	.	.	.	1 to 4 cycles	"3.7 to 29.6 GBq (median, 10.45 GBq)"	MRI assay	"In total, 16 subjects (10 males and 6 females) with a mean age of 55.68 &plusmn; 13.17 years (26-73 years) participated in the study. Of them, 8 patients were new HGG cases, and 8 patients had recurrent tumors. The participants' responses to treatments were complete remission in 12.5% of (n = 2), partial remission in 31.25% (n = 5), disease stability in 18.7% (n = 3), and disease progression in 37.5% (n = 6). In total, pretreatment and posttreatment Karnofsky Performance Score and Eastern Cooperative Oncology Group scores did not improved (P > 0.05). The patients were followed up from 1 month to 26 months (median, 3 months)."	.
REF00164	PDC_00027	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	42.7 months	months	.	.	.	Patients with consecutive patients with small bowel neuroendocrine tumour.	.	.	.	.	Every eight to 12 weeks	7.4 GBq (200 mCi)	68Ga-DOTATATE PET/CT assay	"A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of <sup>177</sup>Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively"	Surgery combined with <sup>177</sup>Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.
REF00164	PDC_00027	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	110 months	months	.	.	.	Patients with consecutive patients with small bowel neuroendocrine tumour.	.	.	.	.	Every eight to 12 weeks	7.4 GBq (200 mCi)	68Ga-DOTATATE PET/CT assay	"A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of <sup>177</sup>Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively"	Surgery combined with <sup>177</sup>Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.
REF00164	PDC_00027	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	1-year overall survival (OS)	97.40%	%	.	.	.	Patients with consecutive patients with small bowel neuroendocrine tumour.	.	.	.	.	Every eight to 12 weeks	7.4 GBq (200 mCi)	68Ga-DOTATATE PET/CT assay	"A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of <sup>177</sup>Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively"	Surgery combined with <sup>177</sup>Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.
REF00164	PDC_00027	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	3-years overall survival (OS)	97.40%	%	.	.	.	Patients with consecutive patients with small bowel neuroendocrine tumour.	.	.	.	.	Every eight to 12 weeks	7.4 GBq (200 mCi)	68Ga-DOTATATE PET/CT assay	"A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of <sup>177</sup>Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively"	Surgery combined with <sup>177</sup>Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.
REF00164	PDC_00027	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	5-years overall survival overall survival (OS)	94.10%	%	.	.	.	Patients with consecutive patients with small bowel neuroendocrine tumour.	.	.	.	.	Every eight to 12 weeks	7.4 GBq (200 mCi)	68Ga-DOTATATE PET/CT assay	"A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of <sup>177</sup>Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively"	Surgery combined with <sup>177</sup>Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.
REF00164	PDC_00027	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 toxicity	41%	%	.	.	.	Patients with consecutive patients with small bowel neuroendocrine tumour.	.	.	.	.	Every eight to 12 weeks	7.4 GBq (200 mCi)	68Ga-DOTATATE PET/CT assay	"A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of <sup>177</sup>Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively"	Surgery combined with <sup>177</sup>Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.
REF00165	PDC_00004	Tumor-induced osteomalacia	.	Identified from the Human Clinical Data	High Expreesion	Sensitivity	87.50%	%	.	.	.	17 patients with hypophosphatemic osteomalacia suspected to be TIO.	.	.	.	.	.	3.7 MBq (0.10 mCi) per kilogram of body weight	18F-OC PET/CT assay	"The 18F-OC PET/CT scans were positive in 14 patients. Furthermore, 4 of 14 patients were scanned with both 18F-OC and 68Ga-DOTATATE PET/CT. Both studies were able to localize the tumor in all 4 patients. In total, 14 patients had surgery to remove the lesions. Postsurgical pathological examination confirmed causative tumors in these patients, whose symptoms diminished promptly. Serum phosphate levels normalized, confirming the diagnosis of TIO. 18F-OC PET/CT sensitivity, specificity, and accuracy were 87.5%, 100%, and 88.2% respectively. 18F-OC PET/CT findings affected patient management in 88.2% of cases."	18F-OC PET/CT scan is useful in the detection of tumors causing TIO. Further studies with larger patient populations are needed to validate the result.
REF00165	PDC_00004	Tumor-induced osteomalacia	.	Identified from the Human Clinical Data	High Expreesion	Specificity	100%	%	.	.	.	17 patients with hypophosphatemic osteomalacia suspected to be TIO.	.	.	.	.	.	3.7 MBq (0.10 mCi) per kilogram of body weight	18F-OC PET/CT assay	"The 18F-OC PET/CT scans were positive in 14 patients. Furthermore, 4 of 14 patients were scanned with both 18F-OC and 68Ga-DOTATATE PET/CT. Both studies were able to localize the tumor in all 4 patients. In total, 14 patients had surgery to remove the lesions. Postsurgical pathological examination confirmed causative tumors in these patients, whose symptoms diminished promptly. Serum phosphate levels normalized, confirming the diagnosis of TIO. 18F-OC PET/CT sensitivity, specificity, and accuracy were 87.5%, 100%, and 88.2% respectively. 18F-OC PET/CT findings affected patient management in 88.2% of cases."	18F-OC PET/CT scan is useful in the detection of tumors causing TIO. Further studies with larger patient populations are needed to validate the result.
REF00165	PDC_00004	Tumor-induced osteomalacia	.	Identified from the Human Clinical Data	High Expreesion	Accuracy	88.20%	%	.	.	.	17 patients with hypophosphatemic osteomalacia suspected to be TIO.	.	.	.	.	.	3.7 MBq (0.10 mCi) per kilogram of body weight	18F-OC PET/CT assay	"The 18F-OC PET/CT scans were positive in 14 patients. Furthermore, 4 of 14 patients were scanned with both 18F-OC and 68Ga-DOTATATE PET/CT. Both studies were able to localize the tumor in all 4 patients. In total, 14 patients had surgery to remove the lesions. Postsurgical pathological examination confirmed causative tumors in these patients, whose symptoms diminished promptly. Serum phosphate levels normalized, confirming the diagnosis of TIO. 18F-OC PET/CT sensitivity, specificity, and accuracy were 87.5%, 100%, and 88.2% respectively. 18F-OC PET/CT findings affected patient management in 88.2% of cases."	18F-OC PET/CT scan is useful in the detection of tumors causing TIO. Further studies with larger patient populations are needed to validate the result.
REF00166	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	10.60-69.00%	%	.	.	.	Metastatic castration-resistant prostate cancer patients.	.	.	.	.	4-6 cycles at 6-12 weekly intervals	2-8 GBq	.	"Although there are some different approaches regarding the use of <sup>177</sup>Lu-PSMA therapy in different countries, this type of therapy is generally safe, with a low toxicity profile. From the oncological point of view, a PSA (prostate specific antigen) decline of &ge;50% was seen in 10.6-69% of patients with mCRPC; whereas progression-free survival (PFS) was reported to be 3-13.7 months in different studies."	"<sup>177</sup>Lu-PSMA therapy is a promising treatment alternative in patients with mCRPC, with good clinical efficacy, even in heavily pretreated patients with multiple lines of systemic therapy. Additionally, the available data regarding <sup>177</sup>Lu-PSMA therapy revealed that this type of therapy is safe, with a low toxicity profile. There is also some preliminary evidence that <sup>177</sup>Lu-PSMA therapy is more effective, if used prior to other systemic therapies, earlier during the disease course. Consequently, this treatment alternative may shift its place from the last treatment step of mCRPC to one of the initial therapy steps for PCa, probably combined with other systemic treatment options in the future."
REF00166	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	3-13.7 months	months	.	.	.	Metastatic castration-resistant prostate cancer patients.	.	.	.	.	4-6 cycles at 6-12 weekly intervals	2-8 GBq	.	"Although there are some different approaches regarding the use of <sup>177</sup>Lu-PSMA therapy in different countries, this type of therapy is generally safe, with a low toxicity profile. From the oncological point of view, a PSA (prostate specific antigen) decline of &ge;50% was seen in 10.6-69% of patients with mCRPC; whereas progression-free survival (PFS) was reported to be 3-13.7 months in different studies."	"<sup>177</sup>Lu-PSMA therapy is a promising treatment alternative in patients with mCRPC, with good clinical efficacy, even in heavily pretreated patients with multiple lines of systemic therapy. Additionally, the available data regarding <sup>177</sup>Lu-PSMA therapy revealed that this type of therapy is safe, with a low toxicity profile. There is also some preliminary evidence that <sup>177</sup>Lu-PSMA therapy is more effective, if used prior to other systemic therapies, earlier during the disease course. Consequently, this treatment alternative may shift its place from the last treatment step of mCRPC to one of the initial therapy steps for PCa, probably combined with other systemic treatment options in the future."
REF00167	PDC_00027	Advanced neuroendocrine tumour	26-year-old man diagnosed with an advanced neuroendocrine tumour.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	38 months	months	.	.	.	.	.	.	.	.	Four doses every eight weeks	7.4 GBq (200 mCi)	.	"We present a 26-year-old man who started with pelvic pain and after a biopsy of a retro-rectal mass observed in a magnetic resonance was diagnosed with an advanced neuroendocrine tumour. After progression to lanreotide, everolimus and sunitinib, treatment with <sup>177</sup>Lu-DOTATATE was initiated, achieving an excellent response with a progression free survival (PFS) of 38 months."	.
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	18.20%	%	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2 cycles	7.4 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Minor response (MR)	6.10%	%	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2 cycles	7.4 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	24.20%	%	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2 cycles	7.4 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	51.50%	%	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2 cycles	7.4 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	48.50%	%	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2 cycles	7.4 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	17 months	months	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2 cycles	7.4 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 toxicity	Hematologic: n=5	.	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2 cycles	7.4 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	18.20%	%	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2-4 cycles	Mean administered activity during re-treatment: 17.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Minor response (MR)	3%	%	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2-4 cycles	Mean administered activity during re-treatment: 17.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	42.40%	%	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2-4 cycles	Mean administered activity during re-treatment: 17.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	33.30%	%	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2-4 cycles	Mean administered activity during re-treatment: 17.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	66.60%	%	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2-4 cycles	Mean administered activity during re-treatment: 17.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	13 months	months	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2-4 cycles	Mean administered activity during re-treatment: 17.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 toxicity	Hematologic: n=7	.	.	.	.	33 patients with neuroendocrine tumour.	.	.	.	.	2-4 cycles	Mean administered activity during re-treatment: 17.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	3.80%	%	.	.	.	26 patients with neuroendocrine tumour.	.	.	.	.	2-5 cycles	Median activity for re-treatment: 16.5 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Minor response (MR)	3.80%	%	.	.	.	26 patients with neuroendocrine tumour.	.	.	.	.	2-5 cycles	Median activity for re-treatment: 16.5 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	76.90%	%	.	.	.	26 patients with neuroendocrine tumour.	.	.	.	.	2-5 cycles	Median activity for re-treatment: 16.5 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	15.40%	%	.	.	.	26 patients with neuroendocrine tumour.	.	.	.	.	2-5 cycles	Median activity for re-treatment: 16.5 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	84.60%	%	.	.	.	26 patients with neuroendocrine tumour.	.	.	.	.	2-5 cycles	Median activity for re-treatment: 16.5 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	22 months	months	.	.	.	26 patients with neuroendocrine tumour.	.	.	.	.	2-5 cycles	Median activity for re-treatment: 16.5 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 toxicity	Renal: n=1; Hematologic: n=1	.	.	.	.	26 patients with neuroendocrine tumour.	.	.	.	.	2-5 cycles	Median activity for re-treatment: 16.5 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	18.9 months	months	.	.	.	15 patients with neuroendocrine tumour.	.	.	.	.	3-6 cycles	Median cumulative activity: 63.9 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 toxicity	Hematologic: n=2	.	.	.	.	15 patients with neuroendocrine tumour.	.	.	.	.	3-6 cycles	Median cumulative activity: 63.9 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00045	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	21.27%	%	.	.	.	29 patients with neuroendocrine tumour.	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00045	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	78.72%	%	.	.	.	29 patients with neuroendocrine tumour.	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00045	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	100%	%	.	.	.	29 patients with neuroendocrine tumour.	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00045	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	17.5 months	months	.	.	.	29 patients with neuroendocrine tumour.	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00045	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 toxicity	Renal: n=1; Hematologic: n=2; Myelodysplastic syndrome: n=1	.	.	.	.	29 patients with neuroendocrine tumour.	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	21.27%	%	.	.	.	18 patients with neuroendocrine tumour.	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	78.72%	%	.	.	.	18 patients with neuroendocrine tumour.	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	100%	%	.	.	.	18 patients with neuroendocrine tumour.	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	17.5 months	months	.	.	.	18 patients with neuroendocrine tumour.	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 toxicity	Renal: n=1; Hematologic: n=2; Myelodysplastic syndrome: n=1	.	.	.	.	18 patients with neuroendocrine tumour.	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00045	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	15.90%	%	.	.	.	Patients with neuroendocrine tumour (Retreatment).	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00045	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	59.10%	%	.	.	.	Patients with neuroendocrine tumour (Retreatment).	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00045	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	25%	%	.	.	.	Patients with neuroendocrine tumour (Retreatment).	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00045	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	75%	%	.	.	.	Patients with neuroendocrine tumour (Retreatment).	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00045	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	17.5 months	months	.	.	.	Patients with neuroendocrine tumour (Retreatment).	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00045	Small bowel neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 toxicity	Renal: n=1; Hematologic: n=2; Myelodysplastic syndrome: n=1	.	.	.	.	Patients with neuroendocrine tumour (Retreatment).	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	15.90%	%	.	.	.	Patients with neuroendocrine tumour (Retreatment).	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	59.10%	%	.	.	.	Patients with neuroendocrine tumour (Retreatment).	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	25%	%	.	.	.	Patients with neuroendocrine tumour (Retreatment).	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	75%	%	.	.	.	Patients with neuroendocrine tumour (Retreatment).	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	17.5 months	months	.	.	.	Patients with neuroendocrine tumour (Retreatment).	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 toxicity	Renal: n=1; Hematologic: n=2; Myelodysplastic syndrome: n=1	.	.	.	.	Patients with neuroendocrine tumour (Retreatment).	.	.	.	.	.	.	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	15.50%	%	.	.	.	168 patients with neuroendocrine tumour.	.	.	.	.	2 cycles	Median cumulative dose: 44.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	59.50%	%	.	.	.	168 patients with neuroendocrine tumour.	.	.	.	.	2 cycles	Median cumulative dose: 44.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	19.60%	%	.	.	.	168 patients with neuroendocrine tumour.	.	.	.	.	2 cycles	Median cumulative dose: 44.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	75%	%	.	.	.	168 patients with neuroendocrine tumour.	.	.	.	.	2 cycles	Median cumulative dose: 44.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	14.6 months	months	.	.	.	168 patients with neuroendocrine tumour.	.	.	.	.	2 cycles	Median cumulative dose: 44.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 toxicity	Hematologic: n=14; Myelodysplastic syndrome: n=2; Acute myeloid leukemia: n=2	.	.	.	.	168 patients with neuroendocrine tumour.	.	.	.	.	2 cycles	Median cumulative dose: 44.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	38.50%	%	.	.	.	13 Re-retreatment neuroendocrine tumour patients.	.	.	.	.	2 cycles	Median cumulative dose: 59.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	53.80%	%	.	.	.	13 Re-retreatment neuroendocrine tumour patients.	.	.	.	.	2 cycles	Median cumulative dose: 59.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	7.70%	%	.	.	.	13 Re-retreatment neuroendocrine tumour patients.	.	.	.	.	2 cycles	Median cumulative dose: 59.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	92.30%	%	.	.	.	13 re-retreatment neuroendocrine tumour patients.	.	.	.	.	2 cycles	Median cumulative dose: 59.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	14.2 months	months	.	.	.	13 Re-retreatment neuroendocrine tumour patients.	.	.	.	.	2 cycles	Median cumulative dose: 59.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 toxicity	Hematologic: n=14; Myelodysplastic syndrome: n=2; Acute myeloid leukemia: n=2	.	.	.	.	13 re-retreatment neuroendocrine tumour patients.	.	.	.	.	2 cycles	Median cumulative dose: 59.7 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	3.10%	%	.	.	.	35 patients with neuroendocrine tumour.	.	.	.	.	1-4 cycles	Median cumulative activity 44 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	81.30%	%	.	.	.	35 patients with neuroendocrine tumour.	.	.	.	.	1-4 cycles	Median cumulative activity 44 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	15.60%	%	.	.	.	35 patients with neuroendocrine tumour.	.	.	.	.	1-4 cycles	Median cumulative activity 44 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	77.10%	%	.	.	.	35 patients with neuroendocrine tumour.	.	.	.	.	1-4 cycles	Median cumulative activity 44 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	6 months	months	.	.	.	35 patients with neuroendocrine tumour.	.	.	.	.	1-4 cycles	Median cumulative activity 44 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00167	PDC_00027	Advanced neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 toxicity	Hematologic: n=1	.	.	.	.	35 patients with neuroendocrine tumour.	.	.	.	.	1-4 cycles	Median cumulative activity 44 GBq	.	"This case report is a good example of the efficacy and safety of salvage therapy with <sup>177</sup>Lu-DOTATATE in heavily pretreated patients after an initial response to PRRT, an especially challenging context with a limited number of alternatives. Currently, <sup>177</sup>Lu-DOTATATE is an established therapeutic option for the treatment of metastatic NETs. However, there is a lack of evidence for salvage therapy. Recently, published studies have shown the efficacy and acceptable tolerance of re-treatment with PRRT. Nevertheless, these studies are heterogeneous and mostly retrospective, with significant differences between them regarding the patients included, the cumulative dose of PRRT, or the radiolabeled drug used."	"In conclusion, our patient is a good example of re-treatment with PRRT, due to its initial response to <sup>177</sup>Lu-DOTATATE, which lasted more than 3 years. In that moment, two additional cycles of PRRT were administered, reaching again partial response without significant toxicity. <sup>177</sup>Lu-DOTATATE is an effective therapy in NETs with an excellent safety profile. There is evidence that salvage therapy following progression to PRRT after a long response is an option in these patients, with high disease control rates and acceptable safety profile. Nevertheless, large prospective randomized studies are needed to confirm these findings."
REF00168	PDC_00027	"Progressive, well-differentiated neuroendocrine tumor"	.	Identified from the Human Clinical Data	High Expreesion	Flushes decrease rate	1.9	.	.	.	.	22 patients with a metastatic midgut neuroendocrine tumour.	.	.	.	.	.	Intended cumulative dose: 29.6 GBq	.	"After PRRT, mean bowel movement frequency (BMF) decreased from 6.1 &plusmn; 3.4 to 4.6 &plusmn; 3.6 per day (P = 0.009). Flushes decreased from 4.3 &plusmn; 2.9 to 2.4 &plusmn; 2.7 flushes per day (P = 0.002). A decrease of BMF of more than 30% occurred in 47% of patients with baseline BMF of 4 or more (n = 17). In patients with &ge;2 episodes of flushing a day (n = 15), 67% of patients had more than 50% decrease of daily flushing. A decrease in urinary 5-hydroxyindolacetic acid excretion of more than 30% was seen in 56% of patients. The European Organization for Research and Treatment of Cancer-Core Module diarrhea subscale score showed a trend toward improvement by an average of 16.7 &plusmn; 33.3 points (P = 0.11)."	PRRT with <sup>177</sup>Lu-DOTATATE effectively reduced diarrhea and flushing in patients with carcinoid syndrome and can be considered for symptomatic treatment of carcinoid syndrome insufficiently controlled with somatostatin analogs.
REF00168	PDC_00027	"Progressive, well-differentiated neuroendocrine tumor"	.	Identified from the Human Clinical Data	High Expreesion	5-hydroxyindolacetic acid decrease rate (&ge;30%)	56.00%	%	.	.	.	22 patients with a metastatic midgut neuroendocrine tumour.	.	.	.	.	.	Intended cumulative dose: 29.6 GBq	.	"After PRRT, mean bowel movement frequency (BMF) decreased from 6.1 &plusmn; 3.4 to 4.6 &plusmn; 3.6 per day (P = 0.009). Flushes decreased from 4.3 &plusmn; 2.9 to 2.4 &plusmn; 2.7 flushes per day (P = 0.002). A decrease of BMF of more than 30% occurred in 47% of patients with baseline BMF of 4 or more (n = 17). In patients with &ge;2 episodes of flushing a day (n = 15), 67% of patients had more than 50% decrease of daily flushing. A decrease in urinary 5-hydroxyindolacetic acid excretion of more than 30% was seen in 56% of patients. The European Organization for Research and Treatment of Cancer-Core Module diarrhea subscale score showed a trend toward improvement by an average of 16.7 &plusmn; 33.3 points (P = 0.11)."	PRRT with <sup>177</sup>Lu-DOTATATE effectively reduced diarrhea and flushing in patients with carcinoid syndrome and can be considered for symptomatic treatment of carcinoid syndrome insufficiently controlled with somatostatin analogs.
REF00169	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	12 months	months	.	.	.	121 metastatic castration-resistant prostate cancer patients.	.	.	.	.	.	Median administered cumulative activity: 20 GBq	.	"The median administered cumulative activity was 20 GBq (3.7-37 GBq). The median follow-up duration was 36 months (6-72 months). The estimated median PFS and OS were 12 months (mo) (95% CI: 10.3-13 mo) and 16 mo (95% CI: 13-17 mo), respectively. Any PSA decline and PSA decline >50% was achieved in 73% and 61% of the patients, respectively. Multivariate analysis revealed only failure to achieve >50% PSA decline as a significant factor associated with a poor PFS. Prognostic factors associated with reduced OS included, failure to experience >50% PSA decline, heavily pre-treated patient cohort who received >2 lines of prior treatment options, and patient sub-group treated with &ge;2 lines of chemotherapy. Patients re-treated with additional treatment options after attaining <sup>177</sup>Lu-PSMA refractory disease showed a remarkably prolonged OS. A significant clinical benefit was achieved post <sup>177</sup>Lu-PSMA-617 RLT. The most common toxicities observed were fatigue (34.7%), followed by nausea (33%), and dry mouth (24.7%)."	"<sup>177</sup>Lu-PSMA-617 RLT is an effective form of therapy in mCRPC patients and confirms the findings of the short-term studies. <sup>177</sup>Lu-PSMA-617 prolongs the overall survival in mCRPC patients heavily pre-treated with chemotherapy, first and second-line anti-androgens, and androgen inhibitor therapies. The delayed toxicity is low and acceptable by most of these patients. Patients who were treated with various other mCRPC-approved compounds before <sup>177</sup>Lu-PSMA-RLT were associated with a significantly shorter OS than that of the patients who received <sup>177</sup>Lu-PSMA RLT at the earlier stages of mCRPC. An aggressive treatment approach, either sequential or in combination with second-generation anti-androgens, chemotherapies, or with investigational 225Ac-PSMA-617 alpha therapies, might prolong the survival of mCRPC patients in the future."
REF00169	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	16 months	months	.	.	.	121 metastatic castration-resistant prostate cancer patients.	.	.	.	.	.	Median administered cumulative activity: 20 GBq	.	"The median administered cumulative activity was 20 GBq (3.7-37 GBq). The median follow-up duration was 36 months (6-72 months). The estimated median PFS and OS were 12 months (mo) (95% CI: 10.3-13 mo) and 16 mo (95% CI: 13-17 mo), respectively. Any PSA decline and PSA decline >50% was achieved in 73% and 61% of the patients, respectively. Multivariate analysis revealed only failure to achieve >50% PSA decline as a significant factor associated with a poor PFS. Prognostic factors associated with reduced OS included, failure to experience >50% PSA decline, heavily pre-treated patient cohort who received >2 lines of prior treatment options, and patient sub-group treated with &ge;2 lines of chemotherapy. Patients re-treated with additional treatment options after attaining <sup>177</sup>Lu-PSMA refractory disease showed a remarkably prolonged OS. A significant clinical benefit was achieved post <sup>177</sup>Lu-PSMA-617 RLT. The most common toxicities observed were fatigue (34.7%), followed by nausea (33%), and dry mouth (24.7%)."	"<sup>177</sup>Lu-PSMA-617 RLT is an effective form of therapy in mCRPC patients and confirms the findings of the short-term studies. <sup>177</sup>Lu-PSMA-617 prolongs the overall survival in mCRPC patients heavily pre-treated with chemotherapy, first and second-line anti-androgens, and androgen inhibitor therapies. The delayed toxicity is low and acceptable by most of these patients. Patients who were treated with various other mCRPC-approved compounds before <sup>177</sup>Lu-PSMA-RLT were associated with a significantly shorter OS than that of the patients who received <sup>177</sup>Lu-PSMA RLT at the earlier stages of mCRPC. An aggressive treatment approach, either sequential or in combination with second-generation anti-androgens, chemotherapies, or with investigational 225Ac-PSMA-617 alpha therapies, might prolong the survival of mCRPC patients in the future."
REF00169	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	73%	%	.	.	.	121 metastatic castration-resistant prostate cancer patients.	.	.	.	.	.	Median administered cumulative activity: 20 GBq	.	"The median administered cumulative activity was 20 GBq (3.7-37 GBq). The median follow-up duration was 36 months (6-72 months). The estimated median PFS and OS were 12 months (mo) (95% CI: 10.3-13 mo) and 16 mo (95% CI: 13-17 mo), respectively. Any PSA decline and PSA decline >50% was achieved in 73% and 61% of the patients, respectively. Multivariate analysis revealed only failure to achieve >50% PSA decline as a significant factor associated with a poor PFS. Prognostic factors associated with reduced OS included, failure to experience >50% PSA decline, heavily pre-treated patient cohort who received >2 lines of prior treatment options, and patient sub-group treated with &ge;2 lines of chemotherapy. Patients re-treated with additional treatment options after attaining <sup>177</sup>Lu-PSMA refractory disease showed a remarkably prolonged OS. A significant clinical benefit was achieved post <sup>177</sup>Lu-PSMA-617 RLT. The most common toxicities observed were fatigue (34.7%), followed by nausea (33%), and dry mouth (24.7%)."	"<sup>177</sup>Lu-PSMA-617 RLT is an effective form of therapy in mCRPC patients and confirms the findings of the short-term studies. <sup>177</sup>Lu-PSMA-617 prolongs the overall survival in mCRPC patients heavily pre-treated with chemotherapy, first and second-line anti-androgens, and androgen inhibitor therapies. The delayed toxicity is low and acceptable by most of these patients. Patients who were treated with various other mCRPC-approved compounds before <sup>177</sup>Lu-PSMA-RLT were associated with a significantly shorter OS than that of the patients who received <sup>177</sup>Lu-PSMA RLT at the earlier stages of mCRPC. An aggressive treatment approach, either sequential or in combination with second-generation anti-androgens, chemotherapies, or with investigational 225Ac-PSMA-617 alpha therapies, might prolong the survival of mCRPC patients in the future."
REF00169	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	61.00%	%	.	.	.	121 metastatic castration-resistant prostate cancer patients.	.	.	.	.	.	Median administered cumulative activity: 20 GBq	.	"The median administered cumulative activity was 20 GBq (3.7-37 GBq). The median follow-up duration was 36 months (6-72 months). The estimated median PFS and OS were 12 months (mo) (95% CI: 10.3-13 mo) and 16 mo (95% CI: 13-17 mo), respectively. Any PSA decline and PSA decline >50% was achieved in 73% and 61% of the patients, respectively. Multivariate analysis revealed only failure to achieve >50% PSA decline as a significant factor associated with a poor PFS. Prognostic factors associated with reduced OS included, failure to experience >50% PSA decline, heavily pre-treated patient cohort who received >2 lines of prior treatment options, and patient sub-group treated with &ge;2 lines of chemotherapy. Patients re-treated with additional treatment options after attaining <sup>177</sup>Lu-PSMA refractory disease showed a remarkably prolonged OS. A significant clinical benefit was achieved post <sup>177</sup>Lu-PSMA-617 RLT. The most common toxicities observed were fatigue (34.7%), followed by nausea (33%), and dry mouth (24.7%)."	"<sup>177</sup>Lu-PSMA-617 RLT is an effective form of therapy in mCRPC patients and confirms the findings of the short-term studies. <sup>177</sup>Lu-PSMA-617 prolongs the overall survival in mCRPC patients heavily pre-treated with chemotherapy, first and second-line anti-androgens, and androgen inhibitor therapies. The delayed toxicity is low and acceptable by most of these patients. Patients who were treated with various other mCRPC-approved compounds before <sup>177</sup>Lu-PSMA-RLT were associated with a significantly shorter OS than that of the patients who received <sup>177</sup>Lu-PSMA RLT at the earlier stages of mCRPC. An aggressive treatment approach, either sequential or in combination with second-generation anti-androgens, chemotherapies, or with investigational 225Ac-PSMA-617 alpha therapies, might prolong the survival of mCRPC patients in the future."
REF00169	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Fatigue	34.70%	%	.	.	.	121 metastatic castration-resistant prostate cancer patients.	.	.	.	.	.	Median administered cumulative activity: 20 GBq	.	"The median administered cumulative activity was 20 GBq (3.7-37 GBq). The median follow-up duration was 36 months (6-72 months). The estimated median PFS and OS were 12 months (mo) (95% CI: 10.3-13 mo) and 16 mo (95% CI: 13-17 mo), respectively. Any PSA decline and PSA decline >50% was achieved in 73% and 61% of the patients, respectively. Multivariate analysis revealed only failure to achieve >50% PSA decline as a significant factor associated with a poor PFS. Prognostic factors associated with reduced OS included, failure to experience >50% PSA decline, heavily pre-treated patient cohort who received >2 lines of prior treatment options, and patient sub-group treated with &ge;2 lines of chemotherapy. Patients re-treated with additional treatment options after attaining <sup>177</sup>Lu-PSMA refractory disease showed a remarkably prolonged OS. A significant clinical benefit was achieved post <sup>177</sup>Lu-PSMA-617 RLT. The most common toxicities observed were fatigue (34.7%), followed by nausea (33%), and dry mouth (24.7%)."	"<sup>177</sup>Lu-PSMA-617 RLT is an effective form of therapy in mCRPC patients and confirms the findings of the short-term studies. <sup>177</sup>Lu-PSMA-617 prolongs the overall survival in mCRPC patients heavily pre-treated with chemotherapy, first and second-line anti-androgens, and androgen inhibitor therapies. The delayed toxicity is low and acceptable by most of these patients. Patients who were treated with various other mCRPC-approved compounds before <sup>177</sup>Lu-PSMA-RLT were associated with a significantly shorter OS than that of the patients who received <sup>177</sup>Lu-PSMA RLT at the earlier stages of mCRPC. An aggressive treatment approach, either sequential or in combination with second-generation anti-androgens, chemotherapies, or with investigational 225Ac-PSMA-617 alpha therapies, might prolong the survival of mCRPC patients in the future."
REF00169	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Nausea	33%	%	.	.	.	121 metastatic castration-resistant prostate cancer patients.	.	.	.	.	.	Median administered cumulative activity: 20 GBq	.	"The median administered cumulative activity was 20 GBq (3.7-37 GBq). The median follow-up duration was 36 months (6-72 months). The estimated median PFS and OS were 12 months (mo) (95% CI: 10.3-13 mo) and 16 mo (95% CI: 13-17 mo), respectively. Any PSA decline and PSA decline >50% was achieved in 73% and 61% of the patients, respectively. Multivariate analysis revealed only failure to achieve >50% PSA decline as a significant factor associated with a poor PFS. Prognostic factors associated with reduced OS included, failure to experience >50% PSA decline, heavily pre-treated patient cohort who received >2 lines of prior treatment options, and patient sub-group treated with &ge;2 lines of chemotherapy. Patients re-treated with additional treatment options after attaining <sup>177</sup>Lu-PSMA refractory disease showed a remarkably prolonged OS. A significant clinical benefit was achieved post <sup>177</sup>Lu-PSMA-617 RLT. The most common toxicities observed were fatigue (34.7%), followed by nausea (33%), and dry mouth (24.7%)."	"<sup>177</sup>Lu-PSMA-617 RLT is an effective form of therapy in mCRPC patients and confirms the findings of the short-term studies. <sup>177</sup>Lu-PSMA-617 prolongs the overall survival in mCRPC patients heavily pre-treated with chemotherapy, first and second-line anti-androgens, and androgen inhibitor therapies. The delayed toxicity is low and acceptable by most of these patients. Patients who were treated with various other mCRPC-approved compounds before <sup>177</sup>Lu-PSMA-RLT were associated with a significantly shorter OS than that of the patients who received <sup>177</sup>Lu-PSMA RLT at the earlier stages of mCRPC. An aggressive treatment approach, either sequential or in combination with second-generation anti-androgens, chemotherapies, or with investigational 225Ac-PSMA-617 alpha therapies, might prolong the survival of mCRPC patients in the future."
REF00169	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Xerostomia rate	24.70%	%	.	.	.	121 metastatic castration-resistant prostate cancer patients.	.	.	.	.	.	Median administered cumulative activity: 20 GBq	.	"The median administered cumulative activity was 20 GBq (3.7-37 GBq). The median follow-up duration was 36 months (6-72 months). The estimated median PFS and OS were 12 months (mo) (95% CI: 10.3-13 mo) and 16 mo (95% CI: 13-17 mo), respectively. Any PSA decline and PSA decline >50% was achieved in 73% and 61% of the patients, respectively. Multivariate analysis revealed only failure to achieve >50% PSA decline as a significant factor associated with a poor PFS. Prognostic factors associated with reduced OS included, failure to experience >50% PSA decline, heavily pre-treated patient cohort who received >2 lines of prior treatment options, and patient sub-group treated with &ge;2 lines of chemotherapy. Patients re-treated with additional treatment options after attaining <sup>177</sup>Lu-PSMA refractory disease showed a remarkably prolonged OS. A significant clinical benefit was achieved post <sup>177</sup>Lu-PSMA-617 RLT. The most common toxicities observed were fatigue (34.7%), followed by nausea (33%), and dry mouth (24.7%)."	"<sup>177</sup>Lu-PSMA-617 RLT is an effective form of therapy in mCRPC patients and confirms the findings of the short-term studies. <sup>177</sup>Lu-PSMA-617 prolongs the overall survival in mCRPC patients heavily pre-treated with chemotherapy, first and second-line anti-androgens, and androgen inhibitor therapies. The delayed toxicity is low and acceptable by most of these patients. Patients who were treated with various other mCRPC-approved compounds before <sup>177</sup>Lu-PSMA-RLT were associated with a significantly shorter OS than that of the patients who received <sup>177</sup>Lu-PSMA RLT at the earlier stages of mCRPC. An aggressive treatment approach, either sequential or in combination with second-generation anti-androgens, chemotherapies, or with investigational 225Ac-PSMA-617 alpha therapies, might prolong the survival of mCRPC patients in the future."
REF00170	PDC_00027	Differentiated thyroid cancer	.	Identified from the Human Clinical Data	High Expreesion	Biochemical response rate	25.30%	%	.	.	.	157 patients with RR-DTC treated with PPRT.	.	.	.	.	.	.	.	"Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with <sup>177</sup>Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported."	"Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events."
REF00170	PDC_00027	Differentiated thyroid cancer	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	10.50%	%	.	.	.	157 patients with RR-DTC treated with PPRT.	.	.	.	.	.	.	.	"Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with <sup>177</sup>Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported."	"Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events."
REF00170	PDC_00027	Medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Biochemical response rate	37.20%	%	.	.	.	220 patients with metastatic medullary thyroid cancer.	.	.	.	.	.	.	.	"Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with <sup>177</sup>Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported."	"Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events."
REF00170	PDC_00027	Medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	10.60%	%	.	.	.	220 patients with metastatic medullary thyroid cancer.	.	.	.	.	.	.	.	"Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with <sup>177</sup>Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported."	"Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events."
REF00170	PDC_00027	Differentiated thyroid cancer	.	Identified from the Human Clinical Data	High Expreesion	Death rate	48.42%	%	.	.	.	95 patients with advanced radioiodine-refractory differentiated thyroid cancer.	.	.	.	.	.	.	.	"Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with <sup>177</sup>Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported."	"Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events."
REF00170	PDC_00027	Medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Death rate	43.75%	%	.	.	.	144 patients with metastatic medullary thyroid carcinoma.	.	.	.	.	.	.	.	"Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with <sup>177</sup>Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported."	"Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events."
REF00170	PDC_00045	Differentiated thyroid cancer	.	Identified from the Human Clinical Data	High Expreesion	Biochemical response rate	25.30%	%	.	.	.	157 patients with RR-DTC treated with PPRT.	.	.	.	.	.	.	.	"Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with <sup>177</sup>Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported."	"Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events."
REF00170	PDC_00045	Differentiated thyroid cancer	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	10.50%	%	.	.	.	157 patients with RR-DTC treated with PPRT.	.	.	.	.	.	.	.	"Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with <sup>177</sup>Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported."	"Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events."
REF00170	PDC_00045	Medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Biochemical response rate	37.20%	%	.	.	.	220 patients with metastatic medullary thyroid cancer.	.	.	.	.	.	.	.	"Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with <sup>177</sup>Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported."	"Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events."
REF00170	PDC_00045	Medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	10.60%	%	.	.	.	220 patients with metastatic medullary thyroid cancer.	.	.	.	.	.	.	.	"Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with <sup>177</sup>Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported."	"Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events."
REF00170	PDC_00045	Differentiated thyroid cancer	.	Identified from the Human Clinical Data	High Expreesion	Death rate	48.42%	%	.	.	.	95 patients with advanced radioiodine-refractory differentiated thyroid cancer.	.	.	.	.	.	.	.	"Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with <sup>177</sup>Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported."	"Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events."
REF00170	PDC_00045	Medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Death rate	43.75%	%	.	.	.	144 patients with metastatic medullary thyroid carcinoma.	.	.	.	.	.	.	.	"Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with <sup>177</sup>Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported."	"Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events."
REF00171	PDC_00027	Neuroendocrine prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline rate	24%	%	.	.	.	A patient with metastatic castration-resistant prostatic cancer.	.	.	.	.	1 cycle	7.4 GBq	68Ga-DOTATATE PET/CT assay	"In follow-up visits, he reported transient bone pain reduction, and interestingly, PSA levels dropped by 24% (from 326 ng/mL to 247.5 ng/mL). The patient was unable to receive the second cycle due to severe fatigue, which was concomitant with abrupt increase in PSA."	"Treatment with <sup>177</sup>Lu-DOTATATE might be beneficial, but due to rarity of this entity, collaborative, multicentric studies are needed to assess the efficacy of this treatment modality. This case also highlights possible usefulness of PRLT even in cases with diffuse bone marrow involvement (not an indication of treatment in the phase III VISION trial)."
REF00172	PDC_00027	SSR positive lung neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	23 months	months	.	.	.	48 patients with neuroendocrine tumour.	.	.	.	.	1-4 cycles	"Median cumulative activity of 27 GBq (range, 6-43 GBq)"	.	"Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (&ge; modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of <sup>177</sup>Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68)."	"In patients with advanced progressive lung NET and satisfactory SSR expression, <sup>177</sup>Lu-DOTATATE is effective and safe, with a high DCR and encouraging PFS and OS. Further prospective studies comparing <sup>177</sup>Lu-DOTATATE with other systemic options are warranted."
REF00172	PDC_00027	SSR positive lung neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	59 months	months	.	.	.	48 patients with neuroendocrine tumour.	.	.	.	.	1-4 cycles	"Median cumulative activity of 27 GBq (range, 6-43 GBq)"	.	"Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (&ge; modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of <sup>177</sup>Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68)."	"In patients with advanced progressive lung NET and satisfactory SSR expression, <sup>177</sup>Lu-DOTATATE is effective and safe, with a high DCR and encouraging PFS and OS. Further prospective studies comparing <sup>177</sup>Lu-DOTATATE with other systemic options are warranted."
REF00172	PDC_00027	SSR positive lung neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	20%	%	.	.	.	40 patients with neuroendocrine tumour with RECIST-measurable disease.	.	.	.	.	1-4 cycles	"Median cumulative activity of 27 GBq (range, 6-43 GBq)"	.	"Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (&ge; modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of <sup>177</sup>Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68)."	"In patients with advanced progressive lung NET and satisfactory SSR expression, <sup>177</sup>Lu-DOTATATE is effective and safe, with a high DCR and encouraging PFS and OS. Further prospective studies comparing <sup>177</sup>Lu-DOTATATE with other systemic options are warranted."
REF00172	PDC_00027	SSR positive lung neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	68%	%	.	.	.	40 patients with neuroendocrine tumour with RECIST-measurable disease.	.	.	.	.	1-4 cycles	"Median cumulative activity of 27 GBq (range, 6-43 GBq)"	.	"Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (&ge; modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of <sup>177</sup>Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68)."	"In patients with advanced progressive lung NET and satisfactory SSR expression, <sup>177</sup>Lu-DOTATATE is effective and safe, with a high DCR and encouraging PFS and OS. Further prospective studies comparing <sup>177</sup>Lu-DOTATATE with other systemic options are warranted."
REF00172	PDC_00027	SSR positive lung neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	12%	%	.	.	.	40 patients with neuroendocrine tumour with RECIST-measurable disease.	.	.	.	.	1-4 cycles	"Median cumulative activity of 27 GBq (range, 6-43 GBq)"	.	"Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (&ge; modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of <sup>177</sup>Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68)."	"In patients with advanced progressive lung NET and satisfactory SSR expression, <sup>177</sup>Lu-DOTATATE is effective and safe, with a high DCR and encouraging PFS and OS. Further prospective studies comparing <sup>177</sup>Lu-DOTATATE with other systemic options are warranted."
REF00172	PDC_00027	SSR positive lung neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	44%	%	.	.	.	39 patients with neuroendocrine tumour with available <sup>68</sup>Ga-DOTATATE PET/CT.	.	.	.	.	1-4 cycles	"Median cumulative activity of 27 GBq (range, 6-43 GBq)"	68Ga-DOTATATE PET/CT assay	"Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (&ge; modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of <sup>177</sup>Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68)."	"In patients with advanced progressive lung NET and satisfactory SSR expression, <sup>177</sup>Lu-DOTATATE is effective and safe, with a high DCR and encouraging PFS and OS. Further prospective studies comparing <sup>177</sup>Lu-DOTATATE with other systemic options are warranted."
REF00172	PDC_00027	SSR positive lung neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	44%	%	.	.	.	39 patients with neuroendocrine tumour with available <sup>68</sup>Ga-DOTATATE PET/CT.	.	.	.	.	1-4 cycles	"Median cumulative activity of 27 GBq (range, 6-43 GBq)"	68Ga-DOTATATE PET/CT assay	"Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (&ge; modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of <sup>177</sup>Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68)."	"In patients with advanced progressive lung NET and satisfactory SSR expression, <sup>177</sup>Lu-DOTATATE is effective and safe, with a high DCR and encouraging PFS and OS. Further prospective studies comparing <sup>177</sup>Lu-DOTATATE with other systemic options are warranted."
REF00172	PDC_00027	SSR positive lung neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	12%	%	.	.	.	39 patients with neuroendocrine tumour with available <sup>68</sup>Ga-DOTATATE PET/CT.	.	.	.	.	1-4 cycles	"Median cumulative activity of 27 GBq (range, 6-43 GBq)"	6AN1831:AN18988Ga-DOTATATE PET/CT assay	"Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (&ge; modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of <sup>177</sup>Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted of 0.51 (95% CI, 0.21-0.68)."	"In patients with advanced progressive lung NET and satisfactory SSR expression, <sup>177</sup>Lu-DOTATATE is effective and safe, with a high DCR and encouraging PFS and OS. Further prospective studies comparing <sup>177</sup>Lu-DOTATATE with other systemic options are warranted."
REF00173	PDC_00027	Advanced paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	25%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00173	PDC_00027	Advanced paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Biochemical response rate	64%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00173	PDC_00027	Advanced paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	84%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00173	PDC_00027	Advanced paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3/4 lymphopenia	11%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00173	PDC_00027	Advanced paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	9%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00173	PDC_00027	Advanced paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Neutropenia	3%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00173	PDC_00027	Advanced paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Nephrotoxicity	4%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00173	PDC_00045	Medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	25%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00173	PDC_00045	Medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Biochemical response rate	64%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00173	PDC_00045	Medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	84%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00173	PDC_00045	Medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3/4 lymphopenia	11%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00173	PDC_00045	Medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	9%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00173	PDC_00045	Medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Neutropenia	3%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00173	PDC_00045	Medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Nephrotoxicity	4%	%	.	.	.	A total of 201 patients with advanced paragangliomas.	.	.	.	.	.	.	.	"Over the past decade, a small number of studies have evaluated the efficacy and safety of PRRT with <sup>177</sup>Lu-DOTA-SSA in patients with metastatic or inoperable paragangliomas [66, 67]. A recent meta-analysis of 12 studies including a total of 201 patients with advanced paragangliomas showed an objective response rate of 25%, biochemical response rate of 64%, and disease control rate of 84% after treatment with PRRT (either 90Y- or <sup>177</sup>Lu-based agents) [67]. The following minimal treatment-related adverse effects were observed: grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia, and nephrotoxicity in 11%, 9%, 3%, and 4% of the patients, respectively."	The clinical applications of radiolabeled SSAs and DOTA-SSA compounds in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and have been integrated into the current management guidelines of NETs. Several studies support the safety and clinical efficacy of FDA-approved radionuclide therapies including <sup>177</sup>Lu-DOTATATE in advanced GEP NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. The utility of SSTR-based imaging in PRRT response assessment and surveillance of NETs remains to be established.
REF00174	PDC_00029	ATM-mutated metastatic castration resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median survival time	15.3 months	months	.	.	.	831 patients with that late-stage form of prostate cancer.	.	.	.	.	.	.	.	"In the 831-person VISION trial, men with that late-stage form of prostate cancer who received <sup>177</sup>Lu-PSMA-617 (Novartis) in addition to best supportive care had a median survival time of 15.3 months, compared with 11.3 months for individuals who received standard treatments alone."	.
REF00175	PDC_00027	Advanced paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	34.1 months	months	.	.	.	47 patients with neuroendocrine tumour.	.	.	.	.	4 cycles	5.5 GBq (150 mCi)	.	"Median follow-up was 63.1 months with a median progression-free survival (PFS) of 34.1 months. However, median overall survival (OS) was not reached at the time of analysis."	"High burden of skeletal and hepatic metastases, non-GEP-NETs, chromogranin A of 4 ULN, unusual metastatic sites, pre-existing and interim ascites are predictors of poor outcomes in patients treated with <sup>177</sup>Lu-Dotatate. These common indicators can be used for the risk stratification and identification of patients most likely to benefit from PRRT."
REF00176	PDC_00027	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	8.90%	%	.	.	.	34 patients with SSTr2-positive progressive locally advanced or metastatic PPGLs.	.	.	.	.	5 cycles	18.5/27.5 GBq	.	"Both 90Y-DOTATOC and <sup>177</sup>Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, <sup>177</sup>Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00027	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	73.50%	%	.	.	.	34 patients with SSTr2-positive progressive locally advanced or metastatic PPGLs.	.	.	.	.	5 cycles	18.5/27.5 GBq	.	"Both 90Y-DOTATOC and <sup>177</sup>Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, <sup>177</sup>Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00027	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	82%	%	.	.	.	34 patients with SSTr2-positive progressive locally advanced or metastatic PPGLs.	.	.	.	.	5 cycles	18.5/27.5 GBq	.	"Both 90Y-DOTATOC and <sup>177</sup>Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, <sup>177</sup>Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00027	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	18%	%	.	.	.	34 patients with SSTr2-positive progressive locally advanced or metastatic PPGLs.	.	.	.	.	5 cycles	18.5/27.5 GBq	.	"Both 90Y-DOTATOC and <sup>177</sup>Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, <sup>177</sup>Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00027	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 hemoglobin toxicity	17%	%	.	.	.	34 patients with SSTr2-positive progressive locally advanced or metastatic PPGLs.	.	.	.	.	5 cycles	18.5/27.5 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00027	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 hemoglobin toxicity	0%	%	.	.	.	34 patients with SSTr2-positive progressive locally advanced or metastatic PPGLs.	.	.	.	.	5 cycles	18.5/27.5 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00027	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 platelets toxicity	0%	%	.	.	.	34 patients with SSTr2-positive progressive locally advanced or metastatic PPGLs.	.	.	.	.	5 cycles	18.5/27.5 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00027	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 platelets toxicity	0%	%	.	.	.	34 patients with SSTr2-positive progressive locally advanced or metastatic PPGLs.	.	.	.	.	5 cycles	18.5/27.5 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00027	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 neutrophils toxicity	17%	%	.	.	.	34 patients with SSTr2-positive progressive locally advanced or metastatic PPGLs.	.	.	.	.	5 cycles	18.5/27.5 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00027	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 neutrophils toxicity	0%	%	.	.	.	34 patients with SSTr2-positive progressive locally advanced or metastatic PPGLs.	.	.	.	.	5 cycles	18.5/27.5 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00027	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 creatinine toxicity	0%	%	.	.	.	34 patients with SSTr2-positive progressive locally advanced or metastatic PPGLs.	.	.	.	.	5 cycles	18.5/27.5 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00027	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 creatinine toxicity	0%	%	.	.	.	34 patients with SSTr2-positive progressive locally advanced or metastatic PPGLs.	.	.	.	.	5 cycles	18.5/27.5 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00045	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	9%	%	.	.	.	12 patients with SSTr2-positive progressive locally advanced or metastatic paragangliomas.	.	.	.	.	5 cycles	7.4 to 11 GBq	.	"Both 90Y-DOTATOC and <sup>177</sup>Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, <sup>177</sup>Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00045	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	72%	%	.	.	.	12 patients with SSTr2-positive progressive locally advanced or metastatic paragangliomas.	.	.	.	.	5 cycles	7.4 to 11 GBq	.	"Both 90Y-DOTATOC and <sup>177</sup>Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, <sup>177</sup>Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00045	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	80%	%	.	.	.	12 patients with SSTr2-positive progressive locally advanced or metastatic paragangliomas.	.	.	.	.	5 cycles	7.4 to 11 GBq	.	"Both 90Y-DOTATOC and <sup>177</sup>Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, <sup>177</sup>Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00045	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	20%	%	.	.	.	12 patients with SSTr2-positive progressive locally advanced or metastatic paragangliomas.	.	.	.	.	5 cycles	7.4 to 11 GBq	.	"Both 90Y-DOTATOC and <sup>177</sup>Lu-DOTATATE PRRT were well tolerated by patients without significant renal or bone marrow toxicity. The median follow-up was 73 months (range 5-146 months). The overall disease control rate (DCR) was 80% [95% confidence interval (CI) 68.9% to 91.9%] with a mean five cycles of therapy. However, <sup>177</sup>Lu-DOTATATE patients showed a longer median overall survival (mOS) than those receiving 90Y-Dotatoc and a better DCR when higher dosages were administered, even if a direct comparison was not carried out. Syndromic patients had a poorer mOS. SDHx mutations did not interfere with treatment efficacy."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00045	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 hemoglobin toxicity	24%	%	.	.	.	12 patients with SSTr2-positive progressive locally advanced or metastatic paragangliomas.	.	.	.	.	5 cycles	7.4 to 11 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00045	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 hemoglobin toxicity	3%	%	.	.	.	12 patients with SSTr2-positive progressive locally advanced or metastatic paragangliomas.	.	.	.	.	5 cycles	7.4 to 11 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00045	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 platelets toxicity	15%	%	.	.	.	12 patients with SSTr2-positive progressive locally advanced or metastatic paragangliomas.	.	.	.	.	5 cycles	7.4 to 11 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00045	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 platelets toxicity	3%	%	.	.	.	12 patients with SSTr2-positive progressive locally advanced or metastatic paragangliomas.	.	.	.	.	5 cycles	7.4 to 11 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00045	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 neutrophils toxicity	6%	%	.	.	.	12 patients with SSTr2-positive progressive locally advanced or metastatic paragangliomas.	.	.	.	.	5 cycles	7.4 to 11 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00045	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 neutrophils toxicity	6%	%	.	.	.	12 patients with SSTr2-positive progressive locally advanced or metastatic paragangliomas.	.	.	.	.	5 cycles	7.4 to 11 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00045	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 creatinine toxicity	6%	%	.	.	.	12 patients with SSTr2-positive progressive locally advanced or metastatic paragangliomas.	.	.	.	.	5 cycles	7.4 to 11 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00176	PDC_00045	Phaeochromocytoma/Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 creatinine toxicity	3%	%	.	.	.	12 patients with SSTr2-positive progressive locally advanced or metastatic paragangliomas.	.	.	.	.	5 cycles	7.4 to 11 GBq	.	"No cases of grade (G) 3/4 bone marrow toxicity were observed in any of the treated patients. G1 and G2 bone marrow toxicity was observed in 19 and 4 patients, respectively. All patients recovered during the interval between cycles, without the need for interference in the treatment schedule. Two patients had G1 renal toxicity and one patient G2 toxicity. The latter patient started treatment (2008) with 1.53 creatinine at baseline and registered a 1.88 creatinine level at the third cycle, at which point therapy was interrupted (cumulative dosage 11.1 GBq <sup>177</sup>Lu-DOTATATE). She still has stable disease after >10 years, but a worsening of renal function led to the need for weekly hemodialysis from 2019. No significant differences in toxicity were reported in patients treated with 90Y-DOTATOC or <sup>177</sup>Lu-DOTATATE."	"In a long-term follow-up of patients with mPPGL, PRRT demonstrated a tolerability and efficacy comparable to those obtained in GEP-NETs. Our results highlight the need for an appropriate cumulative administered dosage to achieve a very prolonged result and underline the importance of specific symptoms and presence of bone lesions as predictive factors. Given the substantial number of patients evaluated over time, the superior mOS of <sup>177</sup>Lu-DOTATATE with respect to 90Y-DOTATOC indicates the former radiopharmaceutical as the better candidate for new prospective studies of single or associated therapies."
REF00178	PDC_00029	Metastatic hormone-sensitive prostate cancer 	68-year-old male with newly diagnosed high-volume metastatic hormone-sensitive prostate cancer.	Identified from the Human Clinical Data	High Expreesion	PSA decline rate	99.80%	%	.	.	.	.	.	.	.	.	Two cycles at 8-weeks intervals	6.0 GBq/cycle	.	"He showed remarkable symptomatic improvement, with complete resolution of pain by 6 wk following the first cycle, and his ECOG performance score improved to zero. At 12 wk after the second cycle, his serum PSA had decreased from 100 ng/ml to 0.25 ng/ml (99.8% reduction from baseline) and repeat 68Ga-PSMA-11 PET/CT showed a near-complete molecular response with a marked reduction in the extent and tracer avidity of the lesions."	"<sup>177</sup>Lu-PSMA-617 appeared to be a feasible, safe, and effective modality for patients with low-volume mHSPC. The excellent biochemical and radiological responses, as well as progression-free survival comparable to that with upfront docetaxel, as observed in our patient, underscore the potential utility of <sup>177</sup>Lu-PSMA-617 in high-volume mHSPC."
REF00179	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	30 month	months	.	.	.	42 patients with neuroendocrine tumour.	.	.	.	.	2-5 cycles at 8-12-week intervals	Median cumulative activity of 29.6 GBq	.	.	A higher baseline PLR was shown to be associated with a negative outcome on PFS after <sup>177</sup>Lu-DOTATATE therapy and is a promising marker for future larger studies.
REF00180	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge; 3 hematologic adverse events	9.30%	%	.	.	.	14 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	140 patients receiving a total of 497 cycles	6.9 GBq/cycle	.	"Significant (grade &ge; 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade &le; 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT."	"Hematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous 223Ra-dichloride treatment show no significant contribution to incidence rates."
REF00180	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Anemia	7.10%	%	.	.	.	14 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	140 patients receiving a total of 497 cycles	6.9 GBq/cycle	.	"Significant (grade &ge; 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade &le; 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT."	"Hematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous 223Ra-dichloride treatment show no significant contribution to incidence rates."
REF00180	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Leukopenia	3.60%	%	.	.	.	14 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	140 patients receiving a total of 497 cycles	6.9 GBq/cycle	.	"Significant (grade &ge; 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade &le; 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT."	"Hematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous 223Ra-dichloride treatment show no significant contribution to incidence rates."
REF00180	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	4.30%	%	.	.	.	14 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	140 patients receiving a total of 497 cycles	6.9 GBq/cycle	.	"Significant (grade &ge; 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade &le; 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT."	"Hematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous 223Ra-dichloride treatment show no significant contribution to incidence rates."
REF00181	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	50.00%	%	.	.	.	10 patients with low-volume metastatic hormone-sensitive prostate cancer.	.	.	.	.	2 cycles	9.0 GBq (range 8.0-9.2 GBq)	68Ga-PSMA-11 PET/CT assay	.	We successfully performed small lesion dosimetry and showed that the tumor sink effect in mHSPC patients is of less concern than was expected. Tumor-to-organ ratio of absorbed dose was high and tumor uptake correlates with PSA response. Additional treatment cycles are legitimate in terms of organ toxicity and could lead to better tumor response.
REF00183	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	C-index	0.71	.	NCT03042312	"This was an open-label, multicenter, prospective trial to assess safety and efficacy of 177Lu-PSMA-617 in patients with metastatic castration resistant prostate cancer."	Phase 2	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"Once every 6-8 weeks, for a maximum of four to six cycles"	6.0-8.5 GBq	68Ga-PSMA-11 PET/CT assay	"The C-index of the overall survival model was 071 (95% CI 069-073). Similar C-indices were achieved at internal validation (071 [069-073]) and external validation (072 [068-076]). The C-index of the PSA-progression-free survival model was 070 (95% CI 068-072). Similar C-indices were achieved at internal validation (070 [068-072]) and external validation (071 [068-074]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (249 months [95% CI 168-273] vs 74 months [40-108]; p<00001) and PSA-progression-free survival (66 months [60-71] vs 25 months [12-38]; p=0022)."	"Also, previously identified risk factors in mCRPC, such as lactate dehydrogenase or albumin, were not available or were not collected systematically and consequently not tested in the models. Similarly, 2-[18F]FDG-PET was available only in a minority of patients in this study and thus could not be tested in the models. Dual-tracer PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG-PET can improve patient selection for <sup>177</sup>Lu-PSMA therapy; however, several steps are required to establish 2-[18F]FDG-PET as a screening tool for <sup>177</sup>Lu-PSMA in practice (ie, confirmation of its prognostic value in a multicentre setting, standardisation of image interpretation, inclusion in drug label and guidelines, and insurance coverage)."
REF00183	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	C-index	0.71	.	NCT03042312	"This was an open-label, multicenter, prospective trial to assess safety and efficacy of 177Lu-PSMA-617 in patients with metastatic castration resistant prostate cancer."	Phase 2	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"Once every 6-8 weeks, for a maximum of four to six cycles"	6.0-8.5 GBq	68Ga-PSMA-11 PET/CT assay	"The C-index of the overall survival model was 071 (95% CI 069-073). Similar C-indices were achieved at internal validation (071 [069-073]) and external validation (072 [068-076]). The C-index of the PSA-progression-free survival model was 070 (95% CI 068-072). Similar C-indices were achieved at internal validation (070 [068-072]) and external validation (071 [068-074]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (249 months [95% CI 168-273] vs 74 months [40-108]; p<00001) and PSA-progression-free survival (66 months [60-71] vs 25 months [12-38]; p=0022)."	"Also, previously identified risk factors in mCRPC, such as lactate dehydrogenase or albumin, were not available or were not collected systematically and consequently not tested in the models. Similarly, 2-[18F]FDG-PET was available only in a minority of patients in this study and thus could not be tested in the models. Dual-tracer PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG-PET can improve patient selection for <sup>177</sup>Lu-PSMA therapy; however, several steps are required to establish 2-[18F]FDG-PET as a screening tool for <sup>177</sup>Lu-PSMA in practice (ie, confirmation of its prognostic value in a multicentre setting, standardisation of image interpretation, inclusion in drug label and guidelines, and insurance coverage)."
REF00183	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	C-index	0.72	.	NCT03042312	"This was an open-label, multicenter, prospective trial to assess safety and efficacy of 177Lu-PSMA-617 in patients with metastatic castration resistant prostate cancer."	Phase 2	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"Once every 6-8 weeks, for a maximum of four to six cycles"	6.0-8.5 GBq	68Ga-PSMA-11 PET/CT assay	"The C-index of the overall survival model was 071 (95% CI 069-073). Similar C-indices were achieved at internal validation (071 [069-073]) and external validation (072 [068-076]). The C-index of the PSA-progression-free survival model was 070 (95% CI 068-072). Similar C-indices were achieved at internal validation (070 [068-072]) and external validation (071 [068-074]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (249 months [95% CI 168-273] vs 74 months [40-108]; p<00001) and PSA-progression-free survival (66 months [60-71] vs 25 months [12-38]; p=0022)."	"Also, previously identified risk factors in mCRPC, such as lactate dehydrogenase or albumin, were not available or were not collected systematically and consequently not tested in the models. Similarly, 2-[18F]FDG-PET was available only in a minority of patients in this study and thus could not be tested in the models. Dual-tracer PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG-PET can improve patient selection for <sup>177</sup>Lu-PSMA therapy; however, several steps are required to establish 2-[18F]FDG-PET as a screening tool for <sup>177</sup>Lu-PSMA in practice (ie, confirmation of its prognostic value in a multicentre setting, standardisation of image interpretation, inclusion in drug label and guidelines, and insurance coverage)."
REF00183	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	24.9 months	months	NCT03042312	"This was an open-label, multicenter, prospective trial to assess safety and efficacy of 177Lu-PSMA-617 in patients with metastatic castration resistant prostate cancer."	Phase 2	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"Once every 6-8 weeks, for a maximum of four to six cycles"	6.0-8.5 GBq	68Ga-PSMA-11 PET/CT assay	"The C-index of the overall survival model was 071 (95% CI 069-073). Similar C-indices were achieved at internal validation (071 [069-073]) and external validation (072 [068-076]). The C-index of the PSA-progression-free survival model was 070 (95% CI 068-072). Similar C-indices were achieved at internal validation (070 [068-072]) and external validation (071 [068-074]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (249 months [95% CI 168-273] vs 74 months [40-108]; p<00001) and PSA-progression-free survival (66 months [60-71] vs 25 months [12-38]; p=0022)."	"Also, previously identified risk factors in mCRPC, such as lactate dehydrogenase or albumin, were not available or were not collected systematically and consequently not tested in the models. Similarly, 2-[18F]FDG-PET was available only in a minority of patients in this study and thus could not be tested in the models. Dual-tracer PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG-PET can improve patient selection for <sup>177</sup>Lu-PSMA therapy; however, several steps are required to establish 2-[18F]FDG-PET as a screening tool for <sup>177</sup>Lu-PSMA in practice (ie, confirmation of its prognostic value in a multicentre setting, standardisation of image interpretation, inclusion in drug label and guidelines, and insurance coverage)."
REF00183	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	6.6 months	months	NCT03042312	"This was an open-label, multicenter, prospective trial to assess safety and efficacy of 177Lu-PSMA-617 in patients with metastatic castration resistant prostate cancer."	Phase 2	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"Once every 6-8 weeks, for a maximum of four to six cycles"	6.0-8.5 GBq	68Ga-PSMA-11 PET/CT assay	"The C-index of the overall survival model was 071 (95% CI 069-073). Similar C-indices were achieved at internal validation (071 [069-073]) and external validation (072 [068-076]). The C-index of the PSA-progression-free survival model was 070 (95% CI 068-072). Similar C-indices were achieved at internal validation (070 [068-072]) and external validation (071 [068-074]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (249 months [95% CI 168-273] vs 74 months [40-108]; p<00001) and PSA-progression-free survival (66 months [60-71] vs 25 months [12-38]; p=0022)."	"Also, previously identified risk factors in mCRPC, such as lactate dehydrogenase or albumin, were not available or were not collected systematically and consequently not tested in the models. Similarly, 2-[18F]FDG-PET was available only in a minority of patients in this study and thus could not be tested in the models. Dual-tracer PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG-PET can improve patient selection for <sup>177</sup>Lu-PSMA therapy; however, several steps are required to establish 2-[18F]FDG-PET as a screening tool for <sup>177</sup>Lu-PSMA in practice (ie, confirmation of its prognostic value in a multicentre setting, standardisation of image interpretation, inclusion in drug label and guidelines, and insurance coverage)."
REF00186	PDC_00027	Primary cardiac paragangliomas	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	13 months	months	.	.	.	47 years old primary cardiac paragangliomas patient.	.	.	.	.	4 cycles	Cumulative activity of 40.7 GBq (1100 mCi)	.	"The patient was treated with personalized <sup>177</sup>Lu-DOTATATE PRRT and showed complete symptomatic and partial anatomical responses, with a progression-free survival of 13 months."	"Cardiac PGL is an exceedingly rare tumor and may lead to hemodynamic compromise. Surgical resection, if indicated, is technically challenging and frequently not feasible. This case demonstrates that personalized <sup>177</sup>Lu-DOTATATE PRRT can be considered as a safe and effective palliative treatment for unresectable MIBG negative tumor which can substantially improve quality of life."
REF00186	PDC_00027	Primary cardiac paragangliomas	.	Identified from the Human Clinical Data	High Expreesion	Platelets decrease rate	137 x 10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	47 years old primary cardiac paragangliomas patient.	.	.	.	.	4 cycles	Cumulative activity of 40.7 GBq (1100 mCi)	.	"At the end of the 4 cycles, fatigue, chest pain and dyspnea resolved, and episodes of tachyarrhythmia disappeared. The dosage of metoprolol and prazocin was considerably reduced, decreasing respectively from 125 mg to 50 mg and 2 mg to 1 mg TID. The chromogranin A decreased from 585 to 205 ng/mL and the serum norepinephrine decreased from 104 to 37 nmol/L after 4 cycles."	"Cardiac PGL is an exceedingly rare tumor and may lead to hemodynamic compromise. Surgical resection, if indicated, is technically challenging and frequently not feasible. This case demonstrates that personalized <sup>177</sup>Lu-DOTATATE PRRT can be considered as a safe and effective palliative treatment for unresectable MIBG negative tumor which can substantially improve quality of life."
REF00186	PDC_00027	Primary cardiac paragangliomas	.	Identified from the Human Clinical Data	High Expreesion	Neutrophils decrease rate	4 x 10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	47 years old primary cardiac paragangliomas patient.	.	.	.	.	4 cycles	Cumulative activity of 40.7 GBq (1100 mCi)	.	"At the end of the 4 cycles, fatigue, chest pain and dyspnea resolved, and episodes of tachyarrhythmia disappeared. The dosage of metoprolol and prazocin was considerably reduced, decreasing respectively from 125 mg to 50 mg and 2 mg to 1 mg TID. The chromogranin A decreased from 585 to 205 ng/mL and the serum norepinephrine decreased from 104 to 37 nmol/L after 4 cycles."	"Cardiac PGL is an exceedingly rare tumor and may lead to hemodynamic compromise. Surgical resection, if indicated, is technically challenging and frequently not feasible. This case demonstrates that personalized <sup>177</sup>Lu-DOTATATE PRRT can be considered as a safe and effective palliative treatment for unresectable MIBG negative tumor which can substantially improve quality of life."
REF00186	PDC_00027	Primary cardiac paragangliomas	.	Identified from the Human Clinical Data	High Expreesion	Hemoglobin increase rate	14 g/L	g/L	.	.	.	47 years old primary cardiac paragangliomas patient.	.	.	.	.	4 cycles	Cumulative activity of 40.7 GBq (1100 mCi)	.	"At the end of the 4 cycles, fatigue, chest pain and dyspnea resolved, and episodes of tachyarrhythmia disappeared. The dosage of metoprolol and prazocin was considerably reduced, decreasing respectively from 125 mg to 50 mg and 2 mg to 1 mg TID. The chromogranin A decreased from 585 to 205 ng/mL and the serum norepinephrine decreased from 104 to 37 nmol/L after 4 cycles."	"Cardiac PGL is an exceedingly rare tumor and may lead to hemodynamic compromise. Surgical resection, if indicated, is technically challenging and frequently not feasible. This case demonstrates that personalized <sup>177</sup>Lu-DOTATATE PRRT can be considered as a safe and effective palliative treatment for unresectable MIBG negative tumor which can substantially improve quality of life."
REF00187	PDC_00027	Primary cardiac paragangliomas	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	7.7 months	months	.	.	.	7 patients with biopsy-proven neuroendocrine tumour.	.	.	.	.	4 cycles	200 mCi (7.4 GBq)	68Ga-DOTATATE PET/CT assay	"The median time from the last cycle to PD was 3.2 months (range, 1.1-4.6 months). The median progression-free survival was 7.7 months (95% confidence interval, 5.7-9.8 months)."	.
REF00187	PDC_00027	Primary cardiac paragangliomas	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	3.2 months	months	.	.	.	7 patients with biopsy-proven neuroendocrine tumour.	.	.	.	.	4 cycles	200 mCi (7.4 GBq)	68Ga-DOTATATE PET/CT assay	"The median time from the last cycle to PD was 3.2 months (range, 1.1-4.6 months). The median progression-free survival was 7.7 months (95% confidence interval, 5.7-9.8 months)."	.
REF00188	PDC_00029	Metastatic castration-resistant prostate cancer	Nude mice LNCaP cells tumor xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Drug uptake dose	17.4% &plusmn; 2.4%	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	.	4.44-5.55 GBq	.	Preclinical cell-binding studies of [<sup>177</sup>Lu]Lu-PSMA-617 revealed specific binding with LNCaP cells of 17.4% &plusmn; 2.4%. The uptake in LnCaP xenografted tumor (nude mice) was 7.5 &plusmn; 2.6% ID/g for &tilde;1.5-2.0 cm3 tumor volume at 24-h post-injection. Post-therapy (24 h) SPECT image of mCRPC patients with prior orchidectomy and various hormone therapy showed specific localization of [<sup>177</sup>Lu]Lu-PSMA-617 in the tumor region.	.
REF00188	PDC_00029	Metastatic castration-resistant prostate cancer	Nude mice LNCaP cells tumor xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Drug uptake dose	7.5 &plusmn; 2.6%	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	.	4.44-5.55 GBq	.	Preclinical cell-binding studies of [<sup>177</sup>Lu]Lu-PSMA-617 revealed specific binding with LNCaP cells of 17.4% &plusmn; 2.4%. The uptake in LnCaP xenografted tumor (nude mice) was 7.5 &plusmn; 2.6% ID/g for &tilde;1.5-2.0 cm3 tumor volume at 24-h post-injection. Post-therapy (24 h) SPECT image of mCRPC patients with prior orchidectomy and various hormone therapy showed specific localization of [<sup>177</sup>Lu]Lu-PSMA-617 in the tumor region.	.
REF00190	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	6.4 months	months	.	.	.	45 patients with progressive metastatic castration-resistant prostate cancer and diffuse bone marrow involvement.	.	.	.	.	4 cycles	7.4 &plusmn; 1.4 GBq	68Ga-PSMA-11 PET/CT assay	"Median imaging-based progression-free survival (PFS) was 6.4 mo (95% CI, 3.0-9.8) and the median overall survival (OS) was 10.2 months (95% CI, 7.2-12.8). The biochemical response translated into a significantly prolonged PFS (12.9 vs. 2.8 mo, p < 0.001) and OS (13.5 vs. 6.7 mo, p < 0.001)."	"Our findings suggest that repeated cycles of RLT with <sup>177</sup>Lu-PSMA-617 can be carried out at an acceptable safety profile in mCRPC patients with diffuse bone marrow involvement. RLT may provide a suitable strategy for prolonged disease control with substantial clinical benefit. After a minimum of two cycles, treatment response translated into significantly longer median OS. Further studies should be carried out to investigate the role of individualized RLT concepts in this advanced stage setting."
REF00190	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	10.2 months	months	.	.	.	45 patients with progressive metastatic castration-resistant prostate cancer and diffuse bone marrow involvement.	.	.	.	.	4 cycles	7.4 &plusmn; 1.4 GBq	68Ga-PSMA-11 PET/CT assay	"Median imaging-based progression-free survival (PFS) was 6.4 mo (95% CI, 3.0-9.8) and the median overall survival (OS) was 10.2 months (95% CI, 7.2-12.8). The biochemical response translated into a significantly prolonged PFS (12.9 vs. 2.8 mo, p < 0.001) and OS (13.5 vs. 6.7 mo, p < 0.001)."	"Our findings suggest that repeated cycles of RLT with <sup>177</sup>Lu-PSMA-617 can be carried out at an acceptable safety profile in mCRPC patients with diffuse bone marrow involvement. RLT may provide a suitable strategy for prolonged disease control with substantial clinical benefit. After a minimum of two cycles, treatment response translated into significantly longer median OS. Further studies should be carried out to investigate the role of individualized RLT concepts in this advanced stage setting."
REF00190	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge; 3 hematological decline	11%	%	.	.	.	45 patients with progressive metastatic castration-resistant prostate cancer and diffuse bone marrow involvement.	.	.	.	.	4 cycles	7.4 &plusmn; 1.4 GBq	68Ga-PSMA-11 PET/CT assay	"Patients with PR on interim imaging after two cycles had a longer median OS compared to patients with stable or progressive disease (15.5 vs. 7.1 mo, p < 0.001). Previous taxane-based chemotherapy (HR 3.21, 95%CI 1.18-8.70, p = 0.02) and baseline LDH levels (HR 1.001, 95%CI 1.000-1.001, p = 0.04) were inversely associated with OS on a Cox-regression analysis. Grade &ge; 3 hematological decline was observed after 22/201 (11%) cycles with anemia, leukopenia and thrombocytopenia in 15/45 (33%), 6/45 (13%) and 8/45 (18%) patients, respectively."	"Our findings suggest that repeated cycles of RLT with <sup>177</sup>Lu-PSMA-617 can be carried out at an acceptable safety profile in mCRPC patients with diffuse bone marrow involvement. RLT may provide a suitable strategy for prolonged disease control with substantial clinical benefit. After a minimum of two cycles, treatment response translated into significantly longer median OS. Further studies should be carried out to investigate the role of individualized RLT concepts in this advanced stage setting."
REF00190	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Anemia	33%	%	.	.	.	45 patients with progressive metastatic castration-resistant prostate cancer and diffuse bone marrow involvement.	.	.	.	.	4 cycles	7.4 &plusmn; 1.4 GBq	68Ga-PSMA-11 PET/CT assay	"Patients with PR on interim imaging after two cycles had a longer median OS compared to patients with stable or progressive disease (15.5 vs. 7.1 mo, p < 0.001). Previous taxane-based chemotherapy (HR 3.21, 95%CI 1.18-8.70, p = 0.02) and baseline LDH levels (HR 1.001, 95%CI 1.000-1.001, p = 0.04) were inversely associated with OS on a Cox-regression analysis. Grade &ge; 3 hematological decline was observed after 22/201 (11%) cycles with anemia, leukopenia and thrombocytopenia in 15/45 (33%), 6/45 (13%) and 8/45 (18%) patients, respectively."	"Our findings suggest that repeated cycles of RLT with <sup>177</sup>Lu-PSMA-617 can be carried out at an acceptable safety profile in mCRPC patients with diffuse bone marrow involvement. RLT may provide a suitable strategy for prolonged disease control with substantial clinical benefit. After a minimum of two cycles, treatment response translated into significantly longer median OS. Further studies should be carried out to investigate the role of individualized RLT concepts in this advanced stage setting."
REF00190	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Leukopenia	13%	%	.	.	.	45 patients with progressive metastatic castration-resistant prostate cancer and diffuse bone marrow involvement.	.	.	.	.	4 cycles	7.4 &plusmn; 1.4 GBq	68Ga-PSMA-11 PET/CT assay	"Patients with PR on interim imaging after two cycles had a longer median OS compared to patients with stable or progressive disease (15.5 vs. 7.1 mo, p < 0.001). Previous taxane-based chemotherapy (HR 3.21, 95%CI 1.18-8.70, p = 0.02) and baseline LDH levels (HR 1.001, 95%CI 1.000-1.001, p = 0.04) were inversely associated with OS on a Cox-regression analysis. Grade &ge; 3 hematological decline was observed after 22/201 (11%) cycles with anemia, leukopenia and thrombocytopenia in 15/45 (33%), 6/45 (13%) and 8/45 (18%) patients, respectively."	"Our findings suggest that repeated cycles of RLT with <sup>177</sup>Lu-PSMA-617 can be carried out at an acceptable safety profile in mCRPC patients with diffuse bone marrow involvement. RLT may provide a suitable strategy for prolonged disease control with substantial clinical benefit. After a minimum of two cycles, treatment response translated into significantly longer median OS. Further studies should be carried out to investigate the role of individualized RLT concepts in this advanced stage setting."
REF00190	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	18%	%	.	.	.	45 patients with progressive metastatic castration-resistant prostate cancer and diffuse bone marrow involvement.	.	.	.	.	4 cycles	7.4 &plusmn; 1.4 GBq	68Ga-PSMA-11 PET/CT assay	"Patients with PR on interim imaging after two cycles had a longer median OS compared to patients with stable or progressive disease (15.5 vs. 7.1 mo, p < 0.001). Previous taxane-based chemotherapy (HR 3.21, 95%CI 1.18-8.70, p = 0.02) and baseline LDH levels (HR 1.001, 95%CI 1.000-1.001, p = 0.04) were inversely associated with OS on a Cox-regression analysis. Grade &ge; 3 hematological decline was observed after 22/201 (11%) cycles with anemia, leukopenia and thrombocytopenia in 15/45 (33%), 6/45 (13%) and 8/45 (18%) patients, respectively."	"Our findings suggest that repeated cycles of RLT with <sup>177</sup>Lu-PSMA-617 can be carried out at an acceptable safety profile in mCRPC patients with diffuse bone marrow involvement. RLT may provide a suitable strategy for prolonged disease control with substantial clinical benefit. After a minimum of two cycles, treatment response translated into significantly longer median OS. Further studies should be carried out to investigate the role of individualized RLT concepts in this advanced stage setting."
REF00191	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	3.8 months	months	.	.	.	25 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of four (iqr: 2-6) cycles every 6-8 weeks	Mean of 7.7 &plusmn; 1.4 GBq/cycle	.	"The median progression-free survival (PFS) was 3.8 months (95% CI 2.3-5.3), and overall survival (OS) was 8.5 months (95% CI 6.2-10.8)."	"The response to radioligand therapy with <sup>177</sup>Lu-PSMA-617 seems to be independent of the presence of early-onset prostate cancer (EOPC); however, the less favorable survival outcome observed in our study may indicate a more aggressive disease course. Expectedly, the safety of LuPSMA-RLT does not seem to be compromised in metastasized castration-resistant EOPC patients. Comparative studies on age at diagnosis of prostate cancer and the patients outcome after LuPSMA-RLT are needed."
REF00191	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	8.5 months	months	.	.	.	25 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of four (iqr: 2-6) cycles every 6-8 weeks	Mean of 7.7 &plusmn; 1.4 GBq/cycle	.	"The median progression-free survival (PFS) was 3.8 months (95% CI 2.3-5.3), and overall survival (OS) was 8.5 months (95% CI 6.2-10.8)."	"The response to radioligand therapy with <sup>177</sup>Lu-PSMA-617 seems to be independent of the presence of early-onset prostate cancer (EOPC); however, the less favorable survival outcome observed in our study may indicate a more aggressive disease course. Expectedly, the safety of LuPSMA-RLT does not seem to be compromised in metastasized castration-resistant EOPC patients. Comparative studies on age at diagnosis of prostate cancer and the patients outcome after LuPSMA-RLT are needed."
REF00191	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	36.00%	%	.	.	.	25 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of four (iqr: 2-6) cycles every 6-8 weeks	Mean of 7.7 &plusmn; 1.4 GBq/cycle	.	"An initial PSA reduction (&ge; 50%) was observed in 9/25 (36%) of patients without being significantly associated with OS (p = 0.601). PSA response (PSA decline &ge;50% at 12 weeks) was observed in 12/25 (48%) of patients and significantly associated with longer OS (16.0 months, 95% CI 7.4-24.6 vs. 4.0 months, 95% CI 1.1-6.9, p = 0.002)."	"The response to radioligand therapy with <sup>177</sup>Lu-PSMA-617 seems to be independent of the presence of early-onset prostate cancer (EOPC); however, the less favorable survival outcome observed in our study may indicate a more aggressive disease course. Expectedly, the safety of LuPSMA-RLT does not seem to be compromised in metastasized castration-resistant EOPC patients. Comparative studies on age at diagnosis of prostate cancer and the patients outcome after LuPSMA-RLT are needed."
REF00191	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	48.00%	%	.	.	.	25 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of four (iqr: 2-6) cycles every 6-8 weeks	Mean of 7.7 &plusmn; 1.4 GBq/cycle	.	"An initial PSA reduction (&ge; 50%) was observed in 9/25 (36%) of patients without being significantly associated with OS (p = 0.601). PSA response (PSA decline &ge;50% at 12 weeks) was observed in 12/25 (48%) of patients and significantly associated with longer OS (16.0 months, 95% CI 7.4-24.6 vs. 4.0 months, 95% CI 1.1-6.9, p = 0.002)."	"The response to radioligand therapy with <sup>177</sup>Lu-PSMA-617 seems to be independent of the presence of early-onset prostate cancer (EOPC); however, the less favorable survival outcome observed in our study may indicate a more aggressive disease course. Expectedly, the safety of LuPSMA-RLT does not seem to be compromised in metastasized castration-resistant EOPC patients. Comparative studies on age at diagnosis of prostate cancer and the patients outcome after LuPSMA-RLT are needed."
REF00191	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Imaging response rate	44%	%	.	.	.	25 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of four (iqr: 2-6) cycles every 6-8 weeks	Mean of 7.7 &plusmn; 1.4 GBq/cycle	68Ga-PSMA-11 PET/CT assay	"Imaging-based response using 68Ga-PSMA-11-PET/CT after two to three cycles was seen in 11/25 (44%). Additionally, responders had a significantly longer median PFS (8.7 months, 95% CI 1.3-16.1 vs. 1.9 months, 95% CI 1.7-2.2, p < 0.001) and OS (16.0 months, 95% CI 7.6-24.4 vs. 4.0 months, 95% CI 0.9-7.1; p = 0.002)."	"The response to radioligand therapy with <sup>177</sup>Lu-PSMA-617 seems to be independent of the presence of early-onset prostate cancer (EOPC); however, the less favorable survival outcome observed in our study may indicate a more aggressive disease course. Expectedly, the safety of LuPSMA-RLT does not seem to be compromised in metastasized castration-resistant EOPC patients. Comparative studies on age at diagnosis of prostate cancer and the patients outcome after LuPSMA-RLT are needed."
REF00191	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge; 3 anemia	12%	%	.	.	.	25 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of four (iqr: 2-6) cycles every 6-8 weeks	Mean of 7.7 &plusmn; 1.4 GBq/cycle	.	"Intra- or post-therapeutic toxicity was graded according to the CTCAE v5.0 criteria. Newly developing grade &ge; 3 anemia, leukopenia, and thrombocytopenia occurred in three (12%), one (4%), and three (12%) patients, respectively. One patient showed renal toxicity (grade &ge; 3) during follow-up. Pain palliation (>2 level VAS decline) was achieved in 9/14 (64%) and performance status improvement (ECOG level decline &ge; 1) in 8/17 (47%) of patients."	"The response to radioligand therapy with <sup>177</sup>Lu-PSMA-617 seems to be independent of the presence of early-onset prostate cancer (EOPC); however, the less favorable survival outcome observed in our study may indicate a more aggressive disease course. Expectedly, the safety of LuPSMA-RLT does not seem to be compromised in metastasized castration-resistant EOPC patients. Comparative studies on age at diagnosis of prostate cancer and the patients outcome after LuPSMA-RLT are needed."
REF00191	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Leukopenia	4%	%	.	.	.	25 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of four (iqr: 2-6) cycles every 6-8 weeks	Mean of 7.7 &plusmn; 1.4 GBq/cycle	.	"Intra- or post-therapeutic toxicity was graded according to the CTCAE v5.0 criteria. Newly developing grade &ge; 3 anemia, leukopenia, and thrombocytopenia occurred in three (12%), one (4%), and three (12%) patients, respectively. One patient showed renal toxicity (grade &ge; 3) during follow-up. Pain palliation (>2 level VAS decline) was achieved in 9/14 (64%) and performance status improvement (ECOG level decline &ge; 1) in 8/17 (47%) of patients."	"The response to radioligand therapy with <sup>177</sup>Lu-PSMA-617 seems to be independent of the presence of early-onset prostate cancer (EOPC); however, the less favorable survival outcome observed in our study may indicate a more aggressive disease course. Expectedly, the safety of LuPSMA-RLT does not seem to be compromised in metastasized castration-resistant EOPC patients. Comparative studies on age at diagnosis of prostate cancer and the patients outcome after LuPSMA-RLT are needed."
REF00191	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	12%	%	.	.	.	25 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of four (iqr: 2-6) cycles every 6-8 weeks	Mean of 7.7 &plusmn; 1.4 GBq/cycle	.	"Intra- or post-therapeutic toxicity was graded according to the CTCAE v5.0 criteria. Newly developing grade &ge; 3 anemia, leukopenia, and thrombocytopenia occurred in three (12%), one (4%), and three (12%) patients, respectively. One patient showed renal toxicity (grade &ge; 3) during follow-up. Pain palliation (>2 level VAS decline) was achieved in 9/14 (64%) and performance status improvement (ECOG level decline &ge; 1) in 8/17 (47%) of patients."	"The response to radioligand therapy with <sup>177</sup>Lu-PSMA-617 seems to be independent of the presence of early-onset prostate cancer (EOPC); however, the less favorable survival outcome observed in our study may indicate a more aggressive disease course. Expectedly, the safety of LuPSMA-RLT does not seem to be compromised in metastasized castration-resistant EOPC patients. Comparative studies on age at diagnosis of prostate cancer and the patients outcome after LuPSMA-RLT are needed."
REF00191	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Pain relief rate	64%	%	.	.	.	25 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of four (iqr: 2-6) cycles every 6-8 weeks	Mean of 7.7 &plusmn; 1.4 GBq/cycle	.	"Intra- or post-therapeutic toxicity was graded according to the CTCAE v5.0 criteria. Newly developing grade &ge; 3 anemia, leukopenia, and thrombocytopenia occurred in three (12%), one (4%), and three (12%) patients, respectively. One patient showed renal toxicity (grade &ge; 3) during follow-up. Pain palliation (>2 level VAS decline) was achieved in 9/14 (64%) and performance status improvement (ECOG level decline &ge; 1) in 8/17 (47%) of patients."	"The response to radioligand therapy with <sup>177</sup>Lu-PSMA-617 seems to be independent of the presence of early-onset prostate cancer (EOPC); however, the less favorable survival outcome observed in our study may indicate a more aggressive disease course. Expectedly, the safety of LuPSMA-RLT does not seem to be compromised in metastasized castration-resistant EOPC patients. Comparative studies on age at diagnosis of prostate cancer and the patients outcome after LuPSMA-RLT are needed."
REF00191	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Rate of ECOG decline	47%	%	.	.	.	25 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of four (iqr: 2-6) cycles every 6-8 weeks	Mean of 7.7 &plusmn; 1.4 GBq/cycle	.	"Intra- or post-therapeutic toxicity was graded according to the CTCAE v5.0 criteria. Newly developing grade &ge; 3 anemia, leukopenia, and thrombocytopenia occurred in three (12%), one (4%), and three (12%) patients, respectively. One patient showed renal toxicity (grade &ge; 3) during follow-up. Pain palliation (>2 level VAS decline) was achieved in 9/14 (64%) and performance status improvement (ECOG level decline &ge; 1) in 8/17 (47%) of patients."	"The response to radioligand therapy with <sup>177</sup>Lu-PSMA-617 seems to be independent of the presence of early-onset prostate cancer (EOPC); however, the less favorable survival outcome observed in our study may indicate a more aggressive disease course. Expectedly, the safety of LuPSMA-RLT does not seem to be compromised in metastasized castration-resistant EOPC patients. Comparative studies on age at diagnosis of prostate cancer and the patients outcome after LuPSMA-RLT are needed."
REF00192	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	8.0 months	months	.	.	.	51 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	12.9 GBq (range: 9.1-16.9)	.	"After a median follow-up of 49 months, the median PFS (95% CI) was 8.0 (5.9-10.1) months. In univariate analysis, responders showing partial remission (PRPSA and PRTLR) had significantly (p < 0.001, each) longer PFS (median: 10.5 and 9.3 months) than non-responders showing either stable or progressive disease (median: 4.0 and 3.5 months)."	"68Ga-PSMA-11 PET-derived response assessment based on normalization of tumoral PSMA expression to normal liver tissue (TLR) may be an appropriate biomarker for monitoring <sup>177</sup>Lu-PSMA-617 RLT in mCRPC patients and predicting survival outcome (PFS) of this treatment modality. Our study indicates the superiority of using liver-normalized tumor SUV values for molecular response assessment in this setting compared to the use of standard tumor SUV measurements, which are widely practiced at present. However, prospective studies with larger patient cohorts are needed to confirm these initial findings."
REF00192	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial biochemical response	61%	%	.	.	.	51 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	12.9 GBq (range: 9.1-16.9)	.	"Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%)."	"68Ga-PSMA-11 PET-derived response assessment based on normalization of tumoral PSMA expression to normal liver tissue (TLR) may be an appropriate biomarker for monitoring <sup>177</sup>Lu-PSMA-617 RLT in mCRPC patients and predicting survival outcome (PFS) of this treatment modality. Our study indicates the superiority of using liver-normalized tumor SUV values for molecular response assessment in this setting compared to the use of standard tumor SUV measurements, which are widely practiced at present. However, prospective studies with larger patient cohorts are needed to confirm these initial findings."
REF00192	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	35%	%	.	.	.	51 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	12.9 GBq (range: 9.1-16.9)	.	"Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%)."	"68Ga-PSMA-11 PET-derived response assessment based on normalization of tumoral PSMA expression to normal liver tissue (TLR) may be an appropriate biomarker for monitoring <sup>177</sup>Lu-PSMA-617 RLT in mCRPC patients and predicting survival outcome (PFS) of this treatment modality. Our study indicates the superiority of using liver-normalized tumor SUV values for molecular response assessment in this setting compared to the use of standard tumor SUV measurements, which are widely practiced at present. However, prospective studies with larger patient cohorts are needed to confirm these initial findings."
REF00192	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	73%	%	.	.	.	51 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	12.9 GBq (range: 9.1-16.9)	Molecular-imaging based response assessed by SUVpeak	"Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%)."	"68Ga-PSMA-11 PET-derived response assessment based on normalization of tumoral PSMA expression to normal liver tissue (TLR) may be an appropriate biomarker for monitoring <sup>177</sup>Lu-PSMA-617 RLT in mCRPC patients and predicting survival outcome (PFS) of this treatment modality. Our study indicates the superiority of using liver-normalized tumor SUV values for molecular response assessment in this setting compared to the use of standard tumor SUV measurements, which are widely practiced at present. However, prospective studies with larger patient cohorts are needed to confirm these initial findings."
REF00192	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	23%	%	.	.	.	51 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	12.9 GBq (range: 9.1-16.9)	Molecular-imaging based response assessed by SUVpeak	"Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%)."	"68Ga-PSMA-11 PET-derived response assessment based on normalization of tumoral PSMA expression to normal liver tissue (TLR) may be an appropriate biomarker for monitoring <sup>177</sup>Lu-PSMA-617 RLT in mCRPC patients and predicting survival outcome (PFS) of this treatment modality. Our study indicates the superiority of using liver-normalized tumor SUV values for molecular response assessment in this setting compared to the use of standard tumor SUV measurements, which are widely practiced at present. However, prospective studies with larger patient cohorts are needed to confirm these initial findings."
REF00192	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	4%	%	.	.	.	51 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	12.9 GBq (range: 9.1-16.9)	Molecular-imaging based response assessed by SUVpeak	"Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%)."	"68Ga-PSMA-11 PET-derived response assessment based on normalization of tumoral PSMA expression to normal liver tissue (TLR) may be an appropriate biomarker for monitoring <sup>177</sup>Lu-PSMA-617 RLT in mCRPC patients and predicting survival outcome (PFS) of this treatment modality. Our study indicates the superiority of using liver-normalized tumor SUV values for molecular response assessment in this setting compared to the use of standard tumor SUV measurements, which are widely practiced at present. However, prospective studies with larger patient cohorts are needed to confirm these initial findings."
REF00192	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	69%	%	.	.	.	51 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	12.9 GBq (range: 9.1-16.9)	TLR gave similar results assay	"Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%)."	"68Ga-PSMA-11 PET-derived response assessment based on normalization of tumoral PSMA expression to normal liver tissue (TLR) may be an appropriate biomarker for monitoring <sup>177</sup>Lu-PSMA-617 RLT in mCRPC patients and predicting survival outcome (PFS) of this treatment modality. Our study indicates the superiority of using liver-normalized tumor SUV values for molecular response assessment in this setting compared to the use of standard tumor SUV measurements, which are widely practiced at present. However, prospective studies with larger patient cohorts are needed to confirm these initial findings."
REF00192	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	25%	%	.	.	.	51 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	12.9 GBq (range: 9.1-16.9)	TLR gave similar results assay	"Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%)."	"68Ga-PSMA-11 PET-derived response assessment based on normalization of tumoral PSMA expression to normal liver tissue (TLR) may be an appropriate biomarker for monitoring <sup>177</sup>Lu-PSMA-617 RLT in mCRPC patients and predicting survival outcome (PFS) of this treatment modality. Our study indicates the superiority of using liver-normalized tumor SUV values for molecular response assessment in this setting compared to the use of standard tumor SUV measurements, which are widely practiced at present. However, prospective studies with larger patient cohorts are needed to confirm these initial findings."
REF00192	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	6%	%	.	.	.	51 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	12.9 GBq (range: 9.1-16.9)	TLR gave similar results assay	"Thirty-one patients (61%) showed partial biochemical response (PRPSA), 18 patients (35%) stable disease (SDPSA), and two patients (4%) progressive disease (PDPSA). Using molecular-imaging based response assessed by SUVpeak, 37 patients (73%) showed partial response (PRSUV), 12 patients (23%) stable disease (SDSUV), and two patients (4%) progressive disease (PDSUV). Response assessment using TLR gave similar results, with PRTLR in 35 patients (69%), SDTLR in 13 patients (25%), and PDTLR in three patients (6%)."	"68Ga-PSMA-11 PET-derived response assessment based on normalization of tumoral PSMA expression to normal liver tissue (TLR) may be an appropriate biomarker for monitoring <sup>177</sup>Lu-PSMA-617 RLT in mCRPC patients and predicting survival outcome (PFS) of this treatment modality. Our study indicates the superiority of using liver-normalized tumor SUV values for molecular response assessment in this setting compared to the use of standard tumor SUV measurements, which are widely practiced at present. However, prospective studies with larger patient cohorts are needed to confirm these initial findings."
REF00193	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	7 months	months	.	.	.	58 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 to 5 cycles	Average administered total cumulative dose of 13.32 GBq	.	"On comparison of the treatment outcome between two groups, significant p value was found for symptomatic responders (58% in Group 1 vs. 85% in Group 2), median PFS (7 months in Group 1 vs. not reached in Group 2), and median OS (8 months in Group 1 vs. 16 months in Group 2), with better outcome in Group 2 patients for these variables."	"Thus, the combination of <sup>177</sup>Lu-PSMA-617 PRLT and AA therapy significantly improved patient's symptoms, PFS and OS as compared to only <sup>177</sup>Lu-PSMA PRLT monotherapy in this study analysis. Based upon this promising observation, future prospective randomized controlled, multicenter clinical trials in a larger number of patients would be warranted to confirm this documented benefit of the combined <sup>177</sup>Lu-PSMA-617 PRLT and AA therapy approach versus <sup>177</sup>Lu-PSMA-617 PRLT monotherapy in patients of mCRPC."
REF00193	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	8 months	months	.	.	.	58 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 to 5 cycles	Average administered total cumulative dose of 13.32 GBq	.	"On comparison of the treatment outcome between two groups, significant p value was found for symptomatic responders (58% in Group 1 vs. 85% in Group 2), median PFS (7 months in Group 1 vs. not reached in Group 2), and median OS (8 months in Group 1 vs. 16 months in Group 2), with better outcome in Group 2 patients for these variables."	"Thus, the combination of <sup>177</sup>Lu-PSMA-617 PRLT and AA therapy significantly improved patient's symptoms, PFS and OS as compared to only <sup>177</sup>Lu-PSMA PRLT monotherapy in this study analysis. Based upon this promising observation, future prospective randomized controlled, multicenter clinical trials in a larger number of patients would be warranted to confirm this documented benefit of the combined <sup>177</sup>Lu-PSMA-617 PRLT and AA therapy approach versus <sup>177</sup>Lu-PSMA-617 PRLT monotherapy in patients of mCRPC."
REF00194	PDC_00029	Adenocarcinoma prostate	61-year-old man diagnosed with adenocarcinoma prostate.	Identified from the Human Clinical Data	High Expreesion	PSA level	0.3 ng/mL	ng/mL	.	.	.	.	.	.	.	.	.	10.36 GBq (280 mCi)	.	"Patient underwent 68Ga-labeled PSMA PET/CT scan after 8 weeks of PSMA-RLT, which revealed complete resolution of bilateral pelvic lymph nodes and PSMA-avid lesions in the prostate. Meanwhile, patients PSA levels have also dropped to 0.3 ng/mL."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	Hemoglobin level	85 g/dL	g/dL	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	54 x 10<sup>9</sup> /L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	Prolonged prothrombin time	25.8 seconds	seconds	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	Prolonged activated partial thromboplastin time	1.63 seconds	seconds	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	Rate of low fibrinogen	0.3 g/L	g/L	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	Fibrin degradation increase rate	400 &micro;g/mL	&micro;g/mL	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	Fibrin degradation increase rate	20 &micro;g/mL	&micro;g/mL	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	Coagulation factors II decrease rate	49%	%	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	Coagulation factors V decrease rate	44%	%	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	Coagulation factors VII decrease rate	97%	%	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	Coagulation factors X decrease rate	81%	%	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	Glutamyl Transferase &gamma;GT	100 UI/L	UI/L	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	Glutamyl Transferase N level	38 UI/L	UI/L	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00195	PDC_00027	Metastatic midgut neuroendocrine tumor	55-year-old woman with metastatic midgut neuroendocrine tumor.	Identified from the Human Clinical Data	High Expreesion	C-reactive protein level	5 mg/L	mg/L	.	.	.	.	.	.	.	.	.	7.4 GBq	.	"Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85g/dL), thrombocytopenia (54 10<sup>9</sup>/L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3g/L), elevated fibrin monomer (>400ug/mL) and elevated fibrin degradation products (>20ug/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (&gamma;GT=100UI/L, N<38UI/L). C-reactive protein was <5mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis."	.
REF00196	PDC_00029	Adenocarcinoma prostate	A 74-year-old man with metastatic prostate cancer.	Identified from the Human Clinical Data	High Expreesion	Bone lesions decrease rate	90%	%	.	.	.	.	.	.	.	.	2 cycles	4 GBq	.	Posttherapy 68Ga-PSMA scan after 2 cycles showed significant decrease in metastatic bone lesions with 90% drop in prostate-specific antigen level from 169 to 16.9 ng/mL.	"Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with <sup>177</sup>Lu-PSMA-617 has shown promising results in patients with metastasized castration-resistant prostate cancer. We report a case of a 74-year-old man with metastatic prostate cancer with comorbidities of diabetes mellitus, hypertension, and chronic kidney disease. In order to minimize radiation burden to kidneys, a lower dose of 4 GBq of <sup>177</sup>Lu-PSMA-617 was prescribed instead of the usual 6 to 7 GBq. There was significant decrease in prostate-specific antigen levels and symptoms. Renal profile remained stable. This case highlights that compromised renal function is not a definite contraindication to radionuclide therapy, and doses can be modified based on risk versus benefits."
REF00198	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	10%	%	.	.	.	100 neuroendocrine tumour patients.	.	.	.	.	4 cycles every 10 weeks	7.4 GBq	.	"Four cycles were completed by 86/100 of patients, 4/100 patients discontinued due to haematotoxicity, and 10/100 patients due to progressive disease. The treatment course was adjusted due to haematotoxicity in 24/100 patients, including postponed next cycle (n = 17), reduced administered activity (n = 13), and both adjustments (n = 10). The most observed haematotoxicity grade was grade 0-1 in 54/100 patients, grade 2 in 38/100 and grade 3-4 in 8/100. Significant differences in baseline leucocyte, neutrophil and platelet counts were observed between grade 0-1 and grade 2. However, the correlation between baseline and lowest observed values was poor to moderate. No differences between haematotoxicity grades and baseline parameters or somatostatin receptor positive tumour volume was observed."	"The incidence of severe haematotoxicity was low with extensive screening and monitoring. The vast majority of patients (96/100) was not restricted in treatment continuation by haematotoxicity; therefore, our selection criteria appeared appropriate for safe PRRT treatment. Baseline parameters showed limited correlation with the degree of decline in haematological values."
REF00198	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 haematotoxicity	38%	%	.	.	.	100 neuroendocrine tumour patients.	.	.	.	.	4 cycles every 10 weeks	7.4 GBq	.	"Four cycles were completed by 86/100 of patients, 4/100 patients discontinued due to haematotoxicity, and 10/100 patients due to progressive disease. The treatment course was adjusted due to haematotoxicity in 24/100 patients, including postponed next cycle (n = 17), reduced administered activity (n = 13), and both adjustments (n = 10). The most observed haematotoxicity grade was grade 0-1 in 54/100 patients, grade 2 in 38/100 and grade 3-4 in 8/100. Significant differences in baseline leucocyte, neutrophil and platelet counts were observed between grade 0-1 and grade 2. However, the correlation between baseline and lowest observed values was poor to moderate. No differences between haematotoxicity grades and baseline parameters or somatostatin receptor positive tumour volume was observed."	"The incidence of severe haematotoxicity was low with extensive screening and monitoring. The vast majority of patients (96/100) was not restricted in treatment continuation by haematotoxicity; therefore, our selection criteria appeared appropriate for safe PRRT treatment. Baseline parameters showed limited correlation with the degree of decline in haematological values."
REF00198	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 3/4 haematotoxicity	8%	%	.	.	.	100 neuroendocrine tumour patients.	.	.	.	.	4 cycles every 10 weeks	7.4 GBq	.	"Four cycles were completed by 86/100 of patients, 4/100 patients discontinued due to haematotoxicity, and 10/100 patients due to progressive disease. The treatment course was adjusted due to haematotoxicity in 24/100 patients, including postponed next cycle (n = 17), reduced administered activity (n = 13), and both adjustments (n = 10). The most observed haematotoxicity grade was grade 0-1 in 54/100 patients, grade 2 in 38/100 and grade 3-4 in 8/100. Significant differences in baseline leucocyte, neutrophil and platelet counts were observed between grade 0-1 and grade 2. However, the correlation between baseline and lowest observed values was poor to moderate. No differences between haematotoxicity grades and baseline parameters or somatostatin receptor positive tumour volume was observed."	"The incidence of severe haematotoxicity was low with extensive screening and monitoring. The vast majority of patients (96/100) was not restricted in treatment continuation by haematotoxicity; therefore, our selection criteria appeared appropriate for safe PRRT treatment. Baseline parameters showed limited correlation with the degree of decline in haematological values."
REF00199	PDC_00027	Midgut neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	48.0 months	months	.	.	.	231 NETTER-1 patients.	.	.	.	.	4 cycles every 8 weeks	7.4 GBq (200 mCi)	.	The secondary endpoint of overall survival was not met: median overall survival was 480 months (95% CI 374-552) in the <sup>177</sup>Lu-Dotatate group and 363 months (259-517) in the control group (HR 084 [95% CI 060-117]; two-sided p=030).	"<sup>177</sup>Lu-Dotatate treatment did not significantly improve median overall survival versus high-dose long-acting octreotide. Despite final overall survival not reaching statistical significance, the 117 month difference in median overall survival with <sup>177</sup>Lu-Dotatate treatment versus high-dose long-acting octreotide alone might be considered clinically relevant. No new safety signals were reported during long-term follow-up."
REF00200	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Best PSA response rate	60%	%	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles every 8 weeks	6.0-7.4 GBq/cycle	.	"Of these, best PSA-RR in the <sup>177</sup>Lu-PSMA-617 arm was 60% (9/15) versus 40% (8/20) in the docetaxel arm."	"<sup>177</sup>Lu-PSMA-617 was demonstrated to be safe and non-inferior to docetaxel in the treatment of mCRPC and could, thus, be potentially employed earlier in the disease course rather than being solely reserved for advanced end-stage disease."
REF00202	PDC_00028	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Mild xerostomia	4%	%	.	.	.	51 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 cycles	"6.1 &plusmn; 1.0 GBq (range, 3.4-7.6 GBq)"	.	"Five patients (3.6%) reported mild, reversible xerostomia. 2 patients (3.9%) in the <sup>177</sup>Lu-PSMA I&T group and 3 (3.4%) in <sup>177</sup>Lu-PSMA-617 groupafter 2-6 cycles of treatment and in follow-up. Xerophthalmia was not reported by any patients. No other adverse symptoms were noticed during the entire follow-up period."	"Both <sup>177</sup>Lu-PSMA I&T and <sup>177</sup>Lu-PSMA-617 PRLT demonstrated favorable safety in mCRPC patients. The highest absorbed doses among healthy organs were in the lacrimal and parotid glands-not, however, resulting in any significant clinical sequel. <sup>177</sup>Lu-PSMA-617 demonstrated a higher absorbed dose to the whole-body and lacrimal glands but a lower renal dose than did <sup>177</sup>Lu-PSMA I&T. The mean absorbed tumor doses were comparable for both <sup>177</sup>Lu-PSMA I&T and <sup>177</sup>Lu-PSMA-617. There was a large interpatient variability in the dosimetry parameters. Therefore, individual patient-based dosimetry seems favorable for personalized PRLT."
REF00202	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Mild xerostomia	3%	%	.	.	.	87 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 cycles	"6.5 &plusmn; 1.1 GBq (range, 3.5-9.0 GBq)"	.	"Five patients (3.6%) reported mild, reversible xerostomia. 2 patients (3.9%) in the <sup>177</sup>Lu-PSMA I&T group and 3 (3.4%) in <sup>177</sup>Lu-PSMA-617 groupafter 2-6 cycles of treatment and in follow-up. Xerophthalmia was not reported by any patients. No other adverse symptoms were noticed during the entire follow-up period."	"Both <sup>177</sup>Lu-PSMA I&T and <sup>177</sup>Lu-PSMA-617 PRLT demonstrated favorable safety in mCRPC patients. The highest absorbed doses among healthy organs were in the lacrimal and parotid glands-not, however, resulting in any significant clinical sequel. <sup>177</sup>Lu-PSMA-617 demonstrated a higher absorbed dose to the whole-body and lacrimal glands but a lower renal dose than did <sup>177</sup>Lu-PSMA I&T. The mean absorbed tumor doses were comparable for both <sup>177</sup>Lu-PSMA I&T and <sup>177</sup>Lu-PSMA-617. There was a large interpatient variability in the dosimetry parameters. Therefore, individual patient-based dosimetry seems favorable for personalized PRLT."
REF00203	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	69.30%	%	.	.	.	508patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A total of 12 studies involving 508 cases of mCRPC were included in this analysis. After the first cycle of treatment, the pooled rate of PSA decline was 69.30% (95% CI: 65.40%73.30%), and that of >50% PSA decline was 35.90% (95% CI: 31.80%40.00%). No significant adverse events were reported in any of the studies."	.
REF00203	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	35.90%	%	.	.	.	508 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A total of 12 studies involving 508 cases of mCRPC were included in this analysis. After the first cycle of treatment, the pooled rate of PSA decline was 69.30% (95% CI: 65.40%73.30%), and that of >50% PSA decline was 35.90% (95% CI: 31.80%40.00%). No significant adverse events were reported in any of the studies."	.
REF00205	PDC_00234	Prostate cancer	LNCaP human prostate cancer cells xenografts in intact male immune-deficient mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Maximum tolerated dose (MTD)	7 mg/kg	mg/kg	.	.	.	.	Prostate carcinoma	LNCaP cell	&tilde; 2.8 h	.	.	4.4 &micro;moles/kg/dose	.	"The maximum tolerated multiday intravenous dose (MTD) of this PSA-TG prodrug is 7 mg/kg (4.4 umoles/kg/dose), which results in a peak serum prodrug concentration of 15.4 &plusmn; 1.1 uM and an elimination half-life of ~2.8 h. After 24 h, less than 0.5% of free L12ADT is observed in the plasma. At this MTD, intratumoral concentration of the PSA-TG prodrug is 640 &plusmn; 80 nM (i.e., 8.5 times the LD50 for LNCaP cells in vitro) and 170 &plusmn; 58 nM for the liberated L12ADT (i.e., 13 times the LD50 for L12ADT in vitro)."	"This approach was initially based upon the discovery by Hans Lilja at the University of Lund, Sweden, that Prostate-Specific Antigen (PSA), besides being a serum marker for prostate cancer detection, is a unique prostate differentiation restricted chymotrypsin-like serine protease whose enzymatic activity, once secreted by normal or malignant prostate epithelial cells into the serum, is inhibited by serum inhibitors. Based upon these results, a collaboration was established between the Lilja laboratory at Lund and the Isaacs laboratory at Hopkins, with Sam Denmeade leading the Hopkins effort to identify specific peptide substrates whose efficient hydrolysis is restricted to PSA. This led to the identification of His-Ser-Ser-Lys-Leu-Gln-x-Leu (i.e., a 7AA peptide where -x- is the PSA cleavage site) as the lead peptide for such PSA-activated prodrug development. As an in vitro proof of principle for such a PSA-activated prodrug approach, we collaborated with Andrew V. Schally, Department of Medicine, Tulane University School of Medicine and Veterans Affairs Medical Center, New Orleans, Louisiana to couple the primary amine of doxorubicin via a peptide bond to the carboxylic acid group of the 7AA lead peptide. These studies documented that such a doxorubicin-peptide prodrug selectively kills cells that express enzymatically active PSA."
REF00205	PDC_00234	Prostate cancer	LNCaP human prostate cancer cells xenografts in intact male immune-deficient mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Peak serum prodrug concentration	15.4 &plusmn; 1.1 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	LNCaP cell	&tilde; 2.8 h	.	.	4.4 &micro;moles/kg/dose	.	"The maximum tolerated multiday intravenous dose (MTD) of this PSA-TG prodrug is 7 mg/kg (4.4 umoles/kg/dose), which results in a peak serum prodrug concentration of 15.4 &plusmn; 1.1 uM and an elimination half-life of ~2.8 h. After 24 h, less than 0.5% of free L12ADT is observed in the plasma. At this MTD, intratumoral concentration of the PSA-TG prodrug is 640 &plusmn; 80 nM (i.e., 8.5 times the LD50 for LNCaP cells in vitro) and 170 &plusmn; 58 nM for the liberated L12ADT (i.e., 13 times the LD50 for L12ADT in vitro)."	"This approach was initially based upon the discovery by Hans Lilja at the University of Lund, Sweden, that Prostate-Specific Antigen (PSA), besides being a serum marker for prostate cancer detection, is a unique prostate differentiation restricted chymotrypsin-like serine protease whose enzymatic activity, once secreted by normal or malignant prostate epithelial cells into the serum, is inhibited by serum inhibitors. Based upon these results, a collaboration was established between the Lilja laboratory at Lund and the Isaacs laboratory at Hopkins, with Sam Denmeade leading the Hopkins effort to identify specific peptide substrates whose efficient hydrolysis is restricted to PSA. This led to the identification of His-Ser-Ser-Lys-Leu-Gln-x-Leu (i.e., a 7AA peptide where -x- is the PSA cleavage site) as the lead peptide for such PSA-activated prodrug development. As an in vitro proof of principle for such a PSA-activated prodrug approach, we collaborated with Andrew V. Schally, Department of Medicine, Tulane University School of Medicine and Veterans Affairs Medical Center, New Orleans, Louisiana to couple the primary amine of doxorubicin via a peptide bond to the carboxylic acid group of the 7AA lead peptide. These studies documented that such a doxorubicin-peptide prodrug selectively kills cells that express enzymatically active PSA."
REF00205	PDC_00210	Prostate cancer	LNCaP human prostate cancer cells xenografts in intact male immune-deficient mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Maximum tolerated dose (MTD)	6 mg/kg	mg/kg	.	.	.	.	Prostate carcinoma	LNCaP cell	&tilde; 40 min	.	.	3.67 &micro;moles/kg/dose	.	"For the HK2-TG prodrug, the maximally tolerated multiday intravenous dose of prodrug is 6 mg/kg (3.67 umoles/kg/dose), which produced a peak serum concentration of ~36 uM and has a half-life of ~40 min. In addition, over a 24 h period, <0.5% of free L12ADT analog is observed in plasma, while, within the cancer, the level of 12ADT-released toxin at this MTD is ~1 uM. The prodrug demonstrated a significant antitumor effect in vivo while being administered, but prolonged intravenous administration is not possible due to local toxicity to tail veins."	"There are at least three additional cancer-associated extracellular proteases as potential candidates for the activation of 12-ADT-based prodrugs. These are Human Glandular Kallikrein 2 (HK2 also known as KLK2), Fibroblast Activation Protein (FAP), and Prostate Specific Membrane Antigen (PSMA also known as FOLH1). HK2 is a trypsin-like protease, uniquely secreted into the extracellular fluid at high enzymatically active levels only by normal and malignant prostate epithelial cells. Like PSA, once in the blood, its enzymatic activity is inhibited by serum protease inhibitors, making it an alternative candidate for prostate-targeted prodrug activation. Another alternative candidate is the serine protease, FAP. This is based upon the studies of W. Nathaniel Brennen, initiated while a graduate student with Sam Denmeade, and then, as a post-doctoral fellow with John Isaacs. Subsequently, Dr. Brennen continued this collaboration when he became an independent faculty investigator at Hopkins. His studies focused on the tumor-promoting activity of the influx within sites of metastatic prostate cancer of tumor-infiltrating host-derived fibroblasts that have a highly increased plasma membrane expression of FAP. FAP is a type II integral membrane serine prolyl protease of the dipeptidyl peptidase IV family, which is characterized by a unique post-prolyl cleavage specificity. Based on its restricted expression and unique substrate requirements, FAP is an ideal potential candidate for prodrug activation. PSMA is highly expressed on the extracellular plasma membranes of prostate cancer cells and, as originally discovered by Warren D. W. Heston, has folate hydrolase enzymatic activity. PSMA expression is also upregulated after ADT in resistant metastatic prostate cancer."
REF00205	PDC_00210	Prostate cancer	LNCaP human prostate cancer cells xenografts in intact male immune-deficient mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Peak serum prodrug concentration	&tilde;36 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	LNCaP cell	&tilde; 40 min	.	.	3.67 &micro;moles/kg/dose	.	"For the HK2-TG prodrug, the maximally tolerated multiday intravenous dose of prodrug is 6 mg/kg (3.67 umoles/kg/dose), which produced a peak serum concentration of ~36 uM and has a half-life of ~40 min. In addition, over a 24 h period, <0.5% of free L12ADT analog is observed in plasma, while, within the cancer, the level of 12ADT-released toxin at this MTD is ~1 uM. The prodrug demonstrated a significant antitumor effect in vivo while being administered, but prolonged intravenous administration is not possible due to local toxicity to tail veins."	"There are at least three additional cancer-associated extracellular proteases as potential candidates for the activation of 12-ADT-based prodrugs. These are Human Glandular Kallikrein 2 (HK2 also known as KLK2), Fibroblast Activation Protein (FAP), and Prostate Specific Membrane Antigen (PSMA also known as FOLH1). HK2 is a trypsin-like protease, uniquely secreted into the extracellular fluid at high enzymatically active levels only by normal and malignant prostate epithelial cells. Like PSA, once in the blood, its enzymatic activity is inhibited by serum protease inhibitors, making it an alternative candidate for prostate-targeted prodrug activation. Another alternative candidate is the serine protease, FAP. This is based upon the studies of W. Nathaniel Brennen, initiated while a graduate student with Sam Denmeade, and then, as a post-doctoral fellow with John Isaacs. Subsequently, Dr. Brennen continued this collaboration when he became an independent faculty investigator at Hopkins. His studies focused on the tumor-promoting activity of the influx within sites of metastatic prostate cancer of tumor-infiltrating host-derived fibroblasts that have a highly increased plasma membrane expression of FAP. FAP is a type II integral membrane serine prolyl protease of the dipeptidyl peptidase IV family, which is characterized by a unique post-prolyl cleavage specificity. Based on its restricted expression and unique substrate requirements, FAP is an ideal potential candidate for prodrug activation. PSMA is highly expressed on the extracellular plasma membranes of prostate cancer cells and, as originally discovered by Warren D. W. Heston, has folate hydrolase enzymatic activity. PSMA expression is also upregulated after ADT in resistant metastatic prostate cancer."
REF00205	PDC_00151	Prostate cancer	LNCaP human prostate cancer cells xenografts in intact male immune-deficient mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Maximum tolerated dose (MTD)	6.8 mg/kg	mg/kg	.	.	.	.	Prostate carcinoma	LNCaP cell	46 h	.	.	4 &micro;moles/kg/dose	.	"For the FAP-TG prodrug, the maximally tolerated multiday intravenous dose of prodrug is 6.8 mg/kg (4 umoles/kg/dose), which produced peak serum concentration of ~35-40 uM, and has a half-life of 4-6 h. In addition, over a 24 h period, <1% of free L12ADT analog is observed in plasma while, within the cancer, the level of S12ADT-released toxin at this MTD is 3-5 uM. The prodrug demonstrated a significant antitumor effect in vivo. The antitumor effect is comparable to that observed with a maximally tolerated multiday intravenous dose of docetaxel, but results in significantly less toxicity."	"There are at least three additional cancer-associated extracellular proteases as potential candidates for the activation of 12-ADT-based prodrugs. These are Human Glandular Kallikrein 2 (HK2 also known as KLK2), Fibroblast Activation Protein (FAP), and Prostate Specific Membrane Antigen (PSMA also known as FOLH1). HK2 is a trypsin-like protease, uniquely secreted into the extracellular fluid at high enzymatically active levels only by normal and malignant prostate epithelial cells. Like PSA, once in the blood, its enzymatic activity is inhibited by serum protease inhibitors, making it an alternative candidate for prostate-targeted prodrug activation. Another alternative candidate is the serine protease, FAP. This is based upon the studies of W. Nathaniel Brennen, initiated while a graduate student with Sam Denmeade, and then, as a post-doctoral fellow with John Isaacs. Subsequently, Dr. Brennen continued this collaboration when he became an independent faculty investigator at Hopkins. His studies focused on the tumor-promoting activity of the influx within sites of metastatic prostate cancer of tumor-infiltrating host-derived fibroblasts that have a highly increased plasma membrane expression of FAP. FAP is a type II integral membrane serine prolyl protease of the dipeptidyl peptidase IV family, which is characterized by a unique post-prolyl cleavage specificity. Based on its restricted expression and unique substrate requirements, FAP is an ideal potential candidate for prodrug activation. PSMA is highly expressed on the extracellular plasma membranes of prostate cancer cells and, as originally discovered by Warren D. W. Heston, has folate hydrolase enzymatic activity. PSMA expression is also upregulated after ADT in resistant metastatic prostate cancer."
REF00205	PDC_00151	Prostate cancer	LNCaP human prostate cancer cells xenografts in intact male immune-deficient mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Peak serum prodrug concentration	&tilde;35-40 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	LNCaP cell	46 h	.	.	4 &micro;moles/kg/dose	.	"For the FAP-TG prodrug, the maximally tolerated multiday intravenous dose of prodrug is 6.8 mg/kg (4 umoles/kg/dose), which produced peak serum concentration of ~35-40 uM, and has a half-life of 4-6 h. In addition, over a 24 h period, <1% of free L12ADT analog is observed in plasma while, within the cancer, the level of S12ADT-released toxin at this MTD is 3-5 uM. The prodrug demonstrated a significant antitumor effect in vivo. The antitumor effect is comparable to that observed with a maximally tolerated multiday intravenous dose of docetaxel, but results in significantly less toxicity."	"There are at least three additional cancer-associated extracellular proteases as potential candidates for the activation of 12-ADT-based prodrugs. These are Human Glandular Kallikrein 2 (HK2 also known as KLK2), Fibroblast Activation Protein (FAP), and Prostate Specific Membrane Antigen (PSMA also known as FOLH1). HK2 is a trypsin-like protease, uniquely secreted into the extracellular fluid at high enzymatically active levels only by normal and malignant prostate epithelial cells. Like PSA, once in the blood, its enzymatic activity is inhibited by serum protease inhibitors, making it an alternative candidate for prostate-targeted prodrug activation. Another alternative candidate is the serine protease, FAP. This is based upon the studies of W. Nathaniel Brennen, initiated while a graduate student with Sam Denmeade, and then, as a post-doctoral fellow with John Isaacs. Subsequently, Dr. Brennen continued this collaboration when he became an independent faculty investigator at Hopkins. His studies focused on the tumor-promoting activity of the influx within sites of metastatic prostate cancer of tumor-infiltrating host-derived fibroblasts that have a highly increased plasma membrane expression of FAP. FAP is a type II integral membrane serine prolyl protease of the dipeptidyl peptidase IV family, which is characterized by a unique post-prolyl cleavage specificity. Based on its restricted expression and unique substrate requirements, FAP is an ideal potential candidate for prodrug activation. PSMA is highly expressed on the extracellular plasma membranes of prostate cancer cells and, as originally discovered by Warren D. W. Heston, has folate hydrolase enzymatic activity. PSMA expression is also upregulated after ADT in resistant metastatic prostate cancer."
REF00205	PDC_00318	Prostate cancer	LNCaP human prostate cancer cells xenografts in intact male immune-deficient mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Maximum tolerated dose (MTD)	56 mg/kg	mg/kg	.	.	.	.	Prostate carcinoma	LNCaP cell	4.9 h	.	.	40 &micro;mole/kg/dose	.	"For the PSMA-TG prodrug, the maximally tolerated multiday intravenous dose of prodrug is 56 mg/kg (i.e., 40 umole/kg/dose), which produced a peak serum concentration of ~800 uM and had a half-life of 4.9 h. In addition, over a 24 h period, <1% of free 12ADTAsp analog is observed in plasma while, within the cancer, the level of released toxin at this MTD is >8 uM. The prodrug demonstrated a significant antitumor effect in vivo. The antitumor effect is comparable to that observed with docetaxel, but results in significantly less toxicity."	"There are at least three additional cancer-associated extracellular proteases as potential candidates for the activation of 12-ADT-based prodrugs. These are Human Glandular Kallikrein 2 (HK2 also known as KLK2), Fibroblast Activation Protein (FAP), and Prostate Specific Membrane Antigen (PSMA also known as FOLH1). HK2 is a trypsin-like protease, uniquely secreted into the extracellular fluid at high enzymatically active levels only by normal and malignant prostate epithelial cells. Like PSA, once in the blood, its enzymatic activity is inhibited by serum protease inhibitors, making it an alternative candidate for prostate-targeted prodrug activation. Another alternative candidate is the serine protease, FAP. This is based upon the studies of W. Nathaniel Brennen, initiated while a graduate student with Sam Denmeade, and then, as a post-doctoral fellow with John Isaacs. Subsequently, Dr. Brennen continued this collaboration when he became an independent faculty investigator at Hopkins. His studies focused on the tumor-promoting activity of the influx within sites of metastatic prostate cancer of tumor-infiltrating host-derived fibroblasts that have a highly increased plasma membrane expression of FAP. FAP is a type II integral membrane serine prolyl protease of the dipeptidyl peptidase IV family, which is characterized by a unique post-prolyl cleavage specificity. Based on its restricted expression and unique substrate requirements, FAP is an ideal potential candidate for prodrug activation. PSMA is highly expressed on the extracellular plasma membranes of prostate cancer cells and, as originally discovered by Warren D. W. Heston, has folate hydrolase enzymatic activity. PSMA expression is also upregulated after ADT in resistant metastatic prostate cancer."
REF00205	PDC_00318	Prostate cancer	LNCaP human prostate cancer cells xenografts in intact male immune-deficient mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Peak serum prodrug concentration	&tilde;800 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	LNCaP cell	4.9 h	.	.	40 &micro;mole/kg/dose	.	"For the PSMA-TG prodrug, the maximally tolerated multiday intravenous dose of prodrug is 56 mg/kg (i.e., 40 umole/kg/dose), which produced a peak serum concentration of ~800 uM and had a half-life of 4.9 h. In addition, over a 24 h period, <1% of free 12ADTAsp analog is observed in plasma while, within the cancer, the level of released toxin at this MTD is >8 uM. The prodrug demonstrated a significant antitumor effect in vivo. The antitumor effect is comparable to that observed with docetaxel, but results in significantly less toxicity."	"There are at least three additional cancer-associated extracellular proteases as potential candidates for the activation of 12-ADT-based prodrugs. These are Human Glandular Kallikrein 2 (HK2 also known as KLK2), Fibroblast Activation Protein (FAP), and Prostate Specific Membrane Antigen (PSMA also known as FOLH1). HK2 is a trypsin-like protease, uniquely secreted into the extracellular fluid at high enzymatically active levels only by normal and malignant prostate epithelial cells. Like PSA, once in the blood, its enzymatic activity is inhibited by serum protease inhibitors, making it an alternative candidate for prostate-targeted prodrug activation. Another alternative candidate is the serine protease, FAP. This is based upon the studies of W. Nathaniel Brennen, initiated while a graduate student with Sam Denmeade, and then, as a post-doctoral fellow with John Isaacs. Subsequently, Dr. Brennen continued this collaboration when he became an independent faculty investigator at Hopkins. His studies focused on the tumor-promoting activity of the influx within sites of metastatic prostate cancer of tumor-infiltrating host-derived fibroblasts that have a highly increased plasma membrane expression of FAP. FAP is a type II integral membrane serine prolyl protease of the dipeptidyl peptidase IV family, which is characterized by a unique post-prolyl cleavage specificity. Based on its restricted expression and unique substrate requirements, FAP is an ideal potential candidate for prodrug activation. PSMA is highly expressed on the extracellular plasma membranes of prostate cancer cells and, as originally discovered by Warren D. W. Heston, has folate hydrolase enzymatic activity. PSMA expression is also upregulated after ADT in resistant metastatic prostate cancer."
REF00206	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Biochemical response according to PCWG3 criteria	59%	%	.	.	.	23 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	16 week	6 GBq (162.16 mCi)	.	"At w16, 16 patients (59%) achieved a biochemical response according to the PCWG3 criteria (mean %PSAw16 -77 &plusmn; 13). Four patients (15%) displayed PSA progression (mean %PSAw16 103 &plusmn; 62), and three patients were biochemically stable (mean %PSAw16 -19 &plusmn; 22). In all patients, the biochemical response status was confirmed in the PSA follow-up. %PSAw16 had no correlation to previous treatments or other relevant pretherapeutic parameters (p &ge; 0.15)"	"This study shows that PSA changes in patients with mCRPC as early as four weeks after the first administration of PSMA-RLT are predictive of both long-term biochemical and PET imaging responses, as well as overall survival. At this early stage, a PSA decrease of at least 30% was found to be more suitable to detect future responders, as well as a longer overall survival compared to the threshold of 50% proposed by the PCWG for long-term biochemical evaluation. An early increase in PSA (+25%) is a strong predictor for biochemical progression and shorter overall survival. Larger prospective studies are warranted to validate these findings and provide criteria for the early assessment of PSMA-RLT, including even more lenient thresholds, as suggested by our explorative retrospective ROC analysis."
REF00206	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA progression	15%	%	.	.	.	23 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	16 week	6 GBq (162.16 mCi)	.	"At w16, 16 patients (59%) achieved a biochemical response according to the PCWG3 criteria (mean %PSAw16 -77 &plusmn; 13). Four patients (15%) displayed PSA progression (mean %PSAw16 103 &plusmn; 62), and three patients were biochemically stable (mean %PSAw16 -19 &plusmn; 22). In all patients, the biochemical response status was confirmed in the PSA follow-up. %PSAw16 had no correlation to previous treatments or other relevant pretherapeutic parameters (p &ge; 0.15)"	"This study shows that PSA changes in patients with mCRPC as early as four weeks after the first administration of PSMA-RLT are predictive of both long-term biochemical and PET imaging responses, as well as overall survival. At this early stage, a PSA decrease of at least 30% was found to be more suitable to detect future responders, as well as a longer overall survival compared to the threshold of 50% proposed by the PCWG for long-term biochemical evaluation. An early increase in PSA (+25%) is a strong predictor for biochemical progression and shorter overall survival. Larger prospective studies are warranted to validate these findings and provide criteria for the early assessment of PSMA-RLT, including even more lenient thresholds, as suggested by our explorative retrospective ROC analysis."
REF00206	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Biochemical response according to PCWG3 criteria	13%	%	.	.	.	23 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	16 week	6 GBq (162.16 mCi)	.	"At w16, 16 patients (59%) achieved a biochemical response according to the PCWG3 criteria (mean %PSAw16 -77 &plusmn; 13). Four patients (15%) displayed PSA progression (mean %PSAw16 103 &plusmn; 62), and three patients were biochemically stable (mean %PSAw16 -19 &plusmn; 22). In all patients, the biochemical response status was confirmed in the PSA follow-up. %PSAw16 had no correlation to previous treatments or other relevant pretherapeutic parameters (p &ge; 0.15)"	"This study shows that PSA changes in patients with mCRPC as early as four weeks after the first administration of PSMA-RLT are predictive of both long-term biochemical and PET imaging responses, as well as overall survival. At this early stage, a PSA decrease of at least 30% was found to be more suitable to detect future responders, as well as a longer overall survival compared to the threshold of 50% proposed by the PCWG for long-term biochemical evaluation. An early increase in PSA (+25%) is a strong predictor for biochemical progression and shorter overall survival. Larger prospective studies are warranted to validate these findings and provide criteria for the early assessment of PSMA-RLT, including even more lenient thresholds, as suggested by our explorative retrospective ROC analysis."
REF00206	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	12.0 months	months	.	.	.	23 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	39.1 months	6 GBq (162.16 mCi)	.	"Patient follow-up was of over 51 months, with the median follow-up (reverse Kaplan-Meier estimator) being 39.1 months (95% CI 32.1-46.1). Median survival was 12.0 (95% CI 10.8-13.2) months, with five patients (19%) still alive at the last follow-up. There were no therapy-related deaths documented. At w16, 14 patients (52%) stated an improvement in pain status from the baseline of at least one tier/level, 11 of which were biochemical responders."	"This study shows that PSA changes in patients with mCRPC as early as four weeks after the first administration of PSMA-RLT are predictive of both long-term biochemical and PET imaging responses, as well as overall survival. At this early stage, a PSA decrease of at least 30% was found to be more suitable to detect future responders, as well as a longer overall survival compared to the threshold of 50% proposed by the PCWG for long-term biochemical evaluation. An early increase in PSA (+25%) is a strong predictor for biochemical progression and shorter overall survival. Larger prospective studies are warranted to validate these findings and provide criteria for the early assessment of PSMA-RLT, including even more lenient thresholds, as suggested by our explorative retrospective ROC analysis."
REF00206	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Survival rate	19%	%	.	.	.	23 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	51 months	6 GBq (162.16 mCi)	.	"Patient follow-up was of over 51 months, with the median follow-up (reverse Kaplan-Meier estimator) being 39.1 months (95% CI 32.1-46.1). Median survival was 12.0 (95% CI 10.8-13.2) months, with five patients (19%) still alive at the last follow-up. There were no therapy-related deaths documented. At w16, 14 patients (52%) stated an improvement in pain status from the baseline of at least one tier/level, 11 of which were biochemical responders."	"This study shows that PSA changes in patients with mCRPC as early as four weeks after the first administration of PSMA-RLT are predictive of both long-term biochemical and PET imaging responses, as well as overall survival. At this early stage, a PSA decrease of at least 30% was found to be more suitable to detect future responders, as well as a longer overall survival compared to the threshold of 50% proposed by the PCWG for long-term biochemical evaluation. An early increase in PSA (+25%) is a strong predictor for biochemical progression and shorter overall survival. Larger prospective studies are warranted to validate these findings and provide criteria for the early assessment of PSMA-RLT, including even more lenient thresholds, as suggested by our explorative retrospective ROC analysis."
REF00206	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Pain relief rate	52%	%	.	.	.	23 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	16 week	6 GBq (162.16 mCi)	.	"Patient follow-up was of over 51 months, with the median follow-up (reverse Kaplan-Meier estimator) being 39.1 months (95% CI 32.1-46.1). Median survival was 12.0 (95% CI 10.8-13.2) months, with five patients (19%) still alive at the last follow-up. There were no therapy-related deaths documented. At w16, 14 patients (52%) stated an improvement in pain status from the baseline of at least one tier/level, 11 of which were biochemical responders."	"This study shows that PSA changes in patients with mCRPC as early as four weeks after the first administration of PSMA-RLT are predictive of both long-term biochemical and PET imaging responses, as well as overall survival. At this early stage, a PSA decrease of at least 30% was found to be more suitable to detect future responders, as well as a longer overall survival compared to the threshold of 50% proposed by the PCWG for long-term biochemical evaluation. An early increase in PSA (+25%) is a strong predictor for biochemical progression and shorter overall survival. Larger prospective studies are warranted to validate these findings and provide criteria for the early assessment of PSMA-RLT, including even more lenient thresholds, as suggested by our explorative retrospective ROC analysis."
REF00207	PDC_00027	Well-differentiated neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	23.52 months	months	.	.	.	82 patients with WD neuroendocrine tumour with a clinical score (CS) less than or equal to 4 points.	.	.	.	.	0 doses	.	.	"Among patients who received 0 doses of PRRT, patients with a CS less than or equal to 4 points experienced a median PFS of 23.52 months (95% CI, 16.76-26.94 months) whereas patients with a CS greater than 4 points experienced a median PFS of 12.55 months (95% CI, 4.99-14.95)."	"Increases in CS were associated with worsening PFS in the validation cohort, validating findings from the original cohort. These findings suggest that the CS, to our knowledge, represents the first clinical metric to estimate anticipated benefit from PRRT for patients with WD NETs and may be a clinical tool for patients being considered for PRRT."
REF00207	PDC_00027	Well-differentiated neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	12.55 months	months	.	.	.	82 patients with WD neuroendocrine tumour with a clinical score (CS) greater than 4 points.	.	.	.	.	0 doses	.	.	"Among patients who received 0 doses of PRRT, patients with a CS less than or equal to 4 points experienced a median PFS of 23.52 months (95% CI, 16.76-26.94 months) whereas patients with a CS greater than 4 points experienced a median PFS of 12.55 months (95% CI, 4.99-14.95)."	"Increases in CS were associated with worsening PFS in the validation cohort, validating findings from the original cohort. These findings suggest that the CS, to our knowledge, represents the first clinical metric to estimate anticipated benefit from PRRT for patients with WD NETs and may be a clinical tool for patients being considered for PRRT."
REF00207	PDC_00027	Well-differentiated neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	27.47 months	months	.	.	.	82 patients with WD neuroendocrine tumour with a clinical score (CS) greater than 4 points.	.	.	.	.	0 doses	.	.	"Among patients who received 0 doses of PRRT, patients with a CS less than or equal to 4 points experienced a median OS of NR (95% CI, NR-NR) whereas patients with a CS greater than 4 points experienced a median OS of 27.47 months (95% CI, 10.35 points to NR)."	"Increases in CS were associated with worsening PFS in the validation cohort, validating findings from the original cohort. These findings suggest that the CS, to our knowledge, represents the first clinical metric to estimate anticipated benefit from PRRT for patients with WD NETs and may be a clinical tool for patients being considered for PRRT."
REF00207	PDC_00027	Well-differentiated neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	6.83 months	months	.	.	.	26 patients with WD neuroendocrine tumour with a clinical score (CS) less than or equal to 4 points.	.	.	.	.	1 or 2 doses	.	.	"Among patients who received 1 or 2 doses of PRRT, patients with a CS less than or equal to 4 points experienced a median PFS of 6.83 months (95% CI, 4.37 months to NR) whereas patients with a CS greater than 4 points experienced a median PFS of 3.06 months (95% CI 1.25-7.16 months."	"Increases in CS were associated with worsening PFS in the validation cohort, validating findings from the original cohort. These findings suggest that the CS, to our knowledge, represents the first clinical metric to estimate anticipated benefit from PRRT for patients with WD NETs and may be a clinical tool for patients being considered for PRRT."
REF00207	PDC_00027	Well-differentiated neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	3.06 months	months	.	.	.	26 patients with WD neuroendocrine tumour with a clinical score (CS) greater than 4 points.	.	.	.	.	1 or 2 doses	.	.	"Among patients who received 1 or 2 doses of PRRT, patients with a CS less than or equal to 4 points experienced a median PFS of 6.83 months (95% CI, 4.37 months to NR) whereas patients with a CS greater than 4 points experienced a median PFS of 3.06 months (95% CI 1.25-7.16 months."	"Increases in CS were associated with worsening PFS in the validation cohort, validating findings from the original cohort. These findings suggest that the CS, to our knowledge, represents the first clinical metric to estimate anticipated benefit from PRRT for patients with WD NETs and may be a clinical tool for patients being considered for PRRT."
REF00207	PDC_00027	Well-differentiated neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	7.98 months	months	.	.	.	26 patients with WD neuroendocrine tumour with a clinical score (CS) less than or equal to 4 points.	.	.	.	.	1 or 2 doses	.	.	"Among patients who received 1 to 2 doses of PRRT, patients with CS less than or equal to 4 points experienced a median OS of 7.98 months (95% CI, 4.37 months to NR) whereas patients with a CS greater than 4 points experienced a median OS of 4.53 months (95% CI, 1.35 months to NR)."	"Increases in CS were associated with worsening PFS in the validation cohort, validating findings from the original cohort. These findings suggest that the CS, to our knowledge, represents the first clinical metric to estimate anticipated benefit from PRRT for patients with WD NETs and may be a clinical tool for patients being considered for PRRT."
REF00207	PDC_00027	Well-differentiated neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	4.53 months	months	.	.	.	26 patients with WD neuroendocrine tumour with a clinical score (CS) greater than 4 points.	.	.	.	.	1 or 2 doses	.	.	"Among patients who received 1 to 2 doses of PRRT, patients with CS less than or equal to 4 points experienced a median OS of 7.98 months (95% CI, 4.37 months to NR) whereas patients with a CS greater than 4 points experienced a median OS of 4.53 months (95% CI, 1.35 months to NR)."	"Increases in CS were associated with worsening PFS in the validation cohort, validating findings from the original cohort. These findings suggest that the CS, to our knowledge, represents the first clinical metric to estimate anticipated benefit from PRRT for patients with WD NETs and may be a clinical tool for patients being considered for PRRT."
REF00207	PDC_00027	Well-differentiated neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	16.92 months	months	.	.	.	140 patients who has well-differentiated neuroendocrine tumor with a clinical score (CS) greater than 4 points.	.	.	.	.	3 or 4 doses	.	.	"Among patients who received 3 or 4 doses of PRRT, patients with a CS less than or equal to 4 points experienced a median PFS of not reached (NR) (95% CI, NR-NR) whereas patients with a CS greater than 4 points experienced a median PFS of 16.92 months (95% CI, 13.50-24.74 months)."	"Increases in CS were associated with worsening PFS in the validation cohort, validating findings from the original cohort. These findings suggest that the CS, to our knowledge, represents the first clinical metric to estimate anticipated benefit from PRRT for patients with WD NETs and may be a clinical tool for patients being considered for PRRT."
REF00208	PDC_00029	Metastatic castration-resistant prostate cancer	"28 men with progressive metastatic castration-resistant prostate cancer who median age 73 years, range 63-89 years)."	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	64.30%	%	.	.	.	.	.	.	.	.	12 weeks after the first cycle	6.5 &plusmn; 1.2 GBq	.	A PSA response (&ge;50% PSA decline 12 weeks after the first<sup>177</sup>Lu-PSMA-617 cycle) was observed in 18/28 (64.3%) patients and imaging-based partial remission (PR) was observed in 11/28 (39.3%) patients.	"RLT with <sup>177</sup>Lu-PSMA-617 can be effectively and safely initiated as early as 8 weeks after failure of 223Ra in patients with progressive bone-metastatic mCRPC refractory to 223Ra. Objective response can be achieved even in patients with more advanced disease and disseminated/diffuse bone metastases, albeit with increasing incidence of significant hematotoxicity."
REF00208	PDC_00029	Metastatic castration-resistant prostate cancer	"28 men with progressive metastatic castration-resistant prostate cancer who median age 73 years, range 63-89 years)."	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	39.30%	%	.	.	.	.	.	.	.	.	12 weeks after the first cycle	6.5 &plusmn; 1.2 GBq	.	A PSA response (&ge;50% PSA decline 12 weeks after the first<sup>177</sup>Lu-PSMA-617 cycle) was observed in 18/28 (64.3%) patients and imaging-based partial remission (PR) was observed in 11/28 (39.3%) patients.	"RLT with <sup>177</sup>Lu-PSMA-617 can be effectively and safely initiated as early as 8 weeks after failure of 223Ra in patients with progressive bone-metastatic mCRPC refractory to 223Ra. Objective response can be achieved even in patients with more advanced disease and disseminated/diffuse bone metastases, albeit with increasing incidence of significant hematotoxicity."
REF00208	PDC_00029	Metastatic castration-resistant prostate cancer	"28 men with progressive metastatic castration-resistant prostate cancer who median age 73 years, range 63-89 years)."	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	10 months	months	.	.	.	.	.	.	.	.	Median of 4 (iqr: 2-7) cycles	Mean cumulative activity of 30.7 &plusmn; 23.4 GBq	.	"Median imaging-based progression-free survival (PFS) was 10 (95% CI, 6-14) months and median overall survival (OS) was 18 (95% CI, 14-22) months."	"RLT with <sup>177</sup>Lu-PSMA-617 can be effectively and safely initiated as early as 8 weeks after failure of 223Ra in patients with progressive bone-metastatic mCRPC refractory to 223Ra. Objective response can be achieved even in patients with more advanced disease and disseminated/diffuse bone metastases, albeit with increasing incidence of significant hematotoxicity."
REF00208	PDC_00029	Metastatic castration-resistant prostate cancer	"28 men with progressive metastatic castration-resistant prostate cancer who median age 73 years, range 63-89 years)."	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	18 months	months	.	.	.	.	.	.	.	.	Median of 4 (iqr: 2-7) cycles	Mean cumulative activity of 30.7 &plusmn; 23.4 GBq	.	"Median imaging-based progression-free survival (PFS) was 10 (95% CI, 6-14) months and median overall survival (OS) was 18 (95% CI, 14-22) months."	"RLT with <sup>177</sup>Lu-PSMA-617 can be effectively and safely initiated as early as 8 weeks after failure of 223Ra in patients with progressive bone-metastatic mCRPC refractory to 223Ra. Objective response can be achieved even in patients with more advanced disease and disseminated/diffuse bone metastases, albeit with increasing incidence of significant hematotoxicity."
REF00208	PDC_00029	Metastatic castration-resistant prostate cancer	"28 men with progressive metastatic castration-resistant prostate cancer who median age 73 years, range 63-89 years)."	Identified from the Human Clinical Data	High Expreesion	Grade &ge; 3 hematological toxicity	21.40%	%	.	.	.	.	.	.	.	.	Median of 4 (iqr: 2-7) cycles	Mean cumulative activity of 30.7 &plusmn; 23.4 GBq	.	"Grade &ge; 3 hematological toxicity was observed in six patients after their last treatment cycle with anemia, leukopenia and thrombocytopenia in 5/28 (17.9%), 4/28 (14.3%) and 6/28 (21.4%) patients, respectively."	"RLT with <sup>177</sup>Lu-PSMA-617 can be effectively and safely initiated as early as 8 weeks after failure of 223Ra in patients with progressive bone-metastatic mCRPC refractory to 223Ra. Objective response can be achieved even in patients with more advanced disease and disseminated/diffuse bone metastases, albeit with increasing incidence of significant hematotoxicity."
REF00208	PDC_00029	Metastatic castration-resistant prostate cancer	"28 men with progressive metastatic castration-resistant prostate cancer who median age 73 years, range 63-89 years)."	Identified from the Human Clinical Data	High Expreesion	Anemia	17.90%	%	.	.	.	.	.	.	.	.	Median of 4 (iqr: 2-7) cycles	Mean cumulative activity of 30.7 &plusmn; 23.4 GBq	.	"Grade &ge; 3 hematological toxicity was observed in six patients after their last treatment cycle with anemia, leukopenia and thrombocytopenia in 5/28 (17.9%), 4/28 (14.3%) and 6/28 (21.4%) patients, respectively."	"RLT with <sup>177</sup>Lu-PSMA-617 can be effectively and safely initiated as early as 8 weeks after failure of 223Ra in patients with progressive bone-metastatic mCRPC refractory to 223Ra. Objective response can be achieved even in patients with more advanced disease and disseminated/diffuse bone metastases, albeit with increasing incidence of significant hematotoxicity."
REF00208	PDC_00029	Metastatic castration-resistant prostate cancer	"28 men with progressive metastatic castration-resistant prostate cancer who median age 73 years, range 63-89 years)."	Identified from the Human Clinical Data	High Expreesion	Leukopenia	14.30%	%	.	.	.	.	.	.	.	.	Median of 4 (iqr: 2-7) cycles	Mean cumulative activity of 30.7 &plusmn; 23.4 GBq	.	"Grade &ge; 3 hematological toxicity was observed in six patients after their last treatment cycle with anemia, leukopenia and thrombocytopenia in 5/28 (17.9%), 4/28 (14.3%) and 6/28 (21.4%) patients, respectively."	"RLT with <sup>177</sup>Lu-PSMA-617 can be effectively and safely initiated as early as 8 weeks after failure of 223Ra in patients with progressive bone-metastatic mCRPC refractory to 223Ra. Objective response can be achieved even in patients with more advanced disease and disseminated/diffuse bone metastases, albeit with increasing incidence of significant hematotoxicity."
REF00208	PDC_00029	Metastatic castration-resistant prostate cancer	"28 men with progressive metastatic castration-resistant prostate cancer who median age 73 years, range 63-89 years)."	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	21.40%	%	.	.	.	.	.	.	.	.	Median of 4 (iqr: 2-7) cycles	Mean cumulative activity of 30.7 &plusmn; 23.4 GBq	.	"Grade &ge; 3 hematological toxicity was observed in six patients after their last treatment cycle with anemia, leukopenia and thrombocytopenia in 5/28 (17.9%), 4/28 (14.3%) and 6/28 (21.4%) patients, respectively."	"RLT with <sup>177</sup>Lu-PSMA-617 can be effectively and safely initiated as early as 8 weeks after failure of 223Ra in patients with progressive bone-metastatic mCRPC refractory to 223Ra. Objective response can be achieved even in patients with more advanced disease and disseminated/diffuse bone metastases, albeit with increasing incidence of significant hematotoxicity."
REF00209	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	21.70%	%	.	.	.	23 GEP neuroendocrine tumours patients.	.	.	.	.	4 cycles	7.4 GBq (200mCi)	.	"PET/CT imaging were done to determine treatment responses 3 months post-PRRT treatment. Only patients who completed 4 cycles (n=23) were included. Five patients (21.7%) showed partial response, 10 patients (43.5 5%) showed stable disease, and 3 patients (13.0%) showed disease progression; the responses from 5 patients (21.7%) were unknown because no PET/CT scan was done."	"From our initial experience, Lutathera has been well tolerated in patients with GEP-NET. Additional studies are needed to examine long-term clinical and patient-reported outcomes associated with treatment of GEP-NETs as well as financial considerations for hospitals embarking on a PRRT program. A multidisciplinary team and complete collaboration between hospital administration and clinical teams are required for successful implementation of a PRRT program."
REF00209	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	43.55%	%	.	.	.	23 GEP neuroendocrine tumours patients.	.	.	.	.	4 cycles	7.4 GBq (200mCi)	.	"PET/CT imaging were done to determine treatment responses 3 months post-PRRT treatment. Only patients who completed 4 cycles (n=23) were included. Five patients (21.7%) showed partial response, 10 patients (43.5 5%) showed stable disease, and 3 patients (13.0%) showed disease progression; the responses from 5 patients (21.7%) were unknown because no PET/CT scan was done."	"From our initial experience, Lutathera has been well tolerated in patients with GEP-NET. Additional studies are needed to examine long-term clinical and patient-reported outcomes associated with treatment of GEP-NETs as well as financial considerations for hospitals embarking on a PRRT program. A multidisciplinary team and complete collaboration between hospital administration and clinical teams are required for successful implementation of a PRRT program."
REF00209	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	13.00%	%	.	.	.	23 GEP neuroendocrine tumours patients.	.	.	.	.	4 cycles	7.4 GBq (200mCi)	.	"PET/CT imaging were done to determine treatment responses 3 months post-PRRT treatment. Only patients who completed 4 cycles (n=23) were included. Five patients (21.7%) showed partial response, 10 patients (43.5 5%) showed stable disease, and 3 patients (13.0%) showed disease progression; the responses from 5 patients (21.7%) were unknown because no PET/CT scan was done."	"From our initial experience, Lutathera has been well tolerated in patients with GEP-NET. Additional studies are needed to examine long-term clinical and patient-reported outcomes associated with treatment of GEP-NETs as well as financial considerations for hospitals embarking on a PRRT program. A multidisciplinary team and complete collaboration between hospital administration and clinical teams are required for successful implementation of a PRRT program."
REF00209	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	CgA levels (95-1000 ng/mL)	66.70%	%	.	.	.	3 patients with GEP neuroendocrine tumour.	.	.	.	.	4 cycles	7.4 GBq (200mCi)	.	"CgA is a marker used in the diagnosis of NETs. Pre-treatment CgA levels were measured in 25 patients. Of the 25 patients, 6 (24.0%), 13 (52.0%), and 6 (24.0%) patients had pretreatment CgA blood level less than 95ng/mL, between 95 and 1000ng/mL, and greater than 1000ng/mL, respectively. After all 4 PRRT cycles were completed; CgA levels were measured in 3 patients. Two (66.7%) patients had post-treatment CgA between 95 and 1000 ng/mL while 1 (33.3%) patient had levels above 1000 ng/mL."	"From our initial experience, Lutathera has been well tolerated in patients with GEP-NET. Additional studies are needed to examine long-term clinical and patient-reported outcomes associated with treatment of GEP-NETs as well as financial considerations for hospitals embarking on a PRRT program. A multidisciplinary team and complete collaboration between hospital administration and clinical teams are required for successful implementation of a PRRT program."
REF00209	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	CgA levels (&ge;1000 ng/mL)	33.30%	%	.	.	.	3 patients with GEP neuroendocrine tumour.	.	.	.	.	4 cycles	7.4 GBq (200mCi)	.	"CgA is a marker used in the diagnosis of NETs. Pre-treatment CgA levels were measured in 25 patients. Of the 25 patients, 6 (24.0%), 13 (52.0%), and 6 (24.0%) patients had pretreatment CgA blood level less than 95ng/mL, between 95 and 1000ng/mL, and greater than 1000ng/mL, respectively. After all 4 PRRT cycles were completed; CgA levels were measured in 3 patients. Two (66.7%) patients had post-treatment CgA between 95 and 1000 ng/mL while 1 (33.3%) patient had levels above 1000 ng/mL."	"From our initial experience, Lutathera has been well tolerated in patients with GEP-NET. Additional studies are needed to examine long-term clinical and patient-reported outcomes associated with treatment of GEP-NETs as well as financial considerations for hospitals embarking on a PRRT program. A multidisciplinary team and complete collaboration between hospital administration and clinical teams are required for successful implementation of a PRRT program."
REF00209	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 adverse events	15.40%	%	.	.	.	13 GEP-neuroendocrine tumour patients.	.	.	.	.	1-4 cycles	7.4 GBq (200mCi)	.	"AE was recorded in 13 patients out of the entire 35 patients treated with PRRT. A grade 5 AE was reported in 2 patients (15.4%) and grade 3 AEs were reported in 5 patients (38.5%). Of the 5 grade 3 AE patients, 1 patient developed ascites, pleural effusion, and acute kidney injury; the second patient developed hematoma at the injection site and pain in the lower extremities; the third patient had shortness of breath, cough, and hemoptysis; the fourth patient had nausea, vomiting, and deep vein thrombosis; and the fifth patient developed obstructive jaundice. All 5 grade 3 AE patients were hospitalized and treated. One patient (7.7%) with a grade 2 AE developed an upper respiratory infection and required antibiotics. Five patients (38.5%) with grade 1 AEs had nausea, vomiting, abdominal pain, and/or diarrhea. No patients developed a grade 4 AE."	"From our initial experience, Lutathera has been well tolerated in patients with GEP-NET. Additional studies are needed to examine long-term clinical and patient-reported outcomes associated with treatment of GEP-NETs as well as financial considerations for hospitals embarking on a PRRT program. A multidisciplinary team and complete collaboration between hospital administration and clinical teams are required for successful implementation of a PRRT program."
REF00209	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 adverse events	38.50%	%	.	.	.	13 GEP-neuroendocrine tumour patients.	.	.	.	.	1-4 cycles	7.4 GBq (200mCi)	.	"AE was recorded in 13 patients out of the entire 35 patients treated with PRRT. A grade 5 AE was reported in 2 patients (15.4%) and grade 3 AEs were reported in 5 patients (38.5%). Of the 5 grade 3 AE patients, 1 patient developed ascites, pleural effusion, and acute kidney injury; the second patient developed hematoma at the injection site and pain in the lower extremities; the third patient had shortness of breath, cough, and hemoptysis; the fourth patient had nausea, vomiting, and deep vein thrombosis; and the fifth patient developed obstructive jaundice. All 5 grade 3 AE patients were hospitalized and treated. One patient (7.7%) with a grade 2 AE developed an upper respiratory infection and required antibiotics. Five patients (38.5%) with grade 1 AEs had nausea, vomiting, abdominal pain, and/or diarrhea. No patients developed a grade 4 AE."	"From our initial experience, Lutathera has been well tolerated in patients with GEP-NET. Additional studies are needed to examine long-term clinical and patient-reported outcomes associated with treatment of GEP-NETs as well as financial considerations for hospitals embarking on a PRRT program. A multidisciplinary team and complete collaboration between hospital administration and clinical teams are required for successful implementation of a PRRT program."
REF00209	PDC_00027	Gastroenteropancreatic neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 adverse events	7.70%	%	.	.	.	13 GEP-neuroendocrine tumour patients.	.	.	.	.	1-4 cycles	7.4 GBq (200mCi)	.	"AE was recorded in 13 patients out of the entire 35 patients treated with PRRT. A grade 5 AE was reported in 2 patients (15.4%) and grade 3 AEs were reported in 5 patients (38.5%). Of the 5 grade 3 AE patients, 1 patient developed ascites, pleural effusion, and acute kidney injury; the second patient developed hematoma at the injection site and pain in the lower extremities; the third patient had shortness of breath, cough, and hemoptysis; the fourth patient had nausea, vomiting, and deep vein thrombosis; and the fifth patient developed obstructive jaundice. All 5 grade 3 AE patients were hospitalized and treated. One patient (7.7%) with a grade 2 AE developed an upper respiratory infection and required antibiotics. Five patients (38.5%) with grade 1 AEs had nausea, vomiting, abdominal pain, and/or diarrhea. No patients developed a grade 4 AE."	"From our initial experience, Lutathera has been well tolerated in patients with GEP-NET. Additional studies are needed to examine long-term clinical and patient-reported outcomes associated with treatment of GEP-NETs as well as financial considerations for hospitals embarking on a PRRT program. A multidisciplinary team and complete collaboration between hospital administration and clinical teams are required for successful implementation of a PRRT program."
REF00210	PDC_00034	Adenocarcinoma prostate	"A 76-year-old nondiabetic man, with adenocarcinoma prostate."	Identified from the Human Clinical Data	High Expreesion	PSA decline	41.6 ng/mL	ng/mL	.	.	.	.	.	.	.	.	2 cycles	8.0 MBq/cycle	.	"In view of refractory disease, the patient was administered 2 cycles of 225Ac-PSMA-617 (8.0 MBq/cycle) intravenously at 8 weeks intervals. Eight weeks following the second cycle, his serum PSA declined from 41.7 ng/mL to 0.1 ng/mL, and a repeat 68Ga-PSMA-11 PET/CT showed complete response."	"<sup>177</sup>Lu-PSMA-617 radioligand therapy (RLT) has evolved as a suitable alternative to existing therapeutic options in patients with metastatic castration-resistant prostate cancer. With the emergence of -emitters such as 225Ac, the efficacy of PSMA-RLT has further improved. Xerostomia and myelosuppression are common early treatment-emergent adverse events in patients receiving this therapy."
REF00210	PDC_00034	Adenocarcinoma prostate	"A 76-year-old nondiabetic man, with adenocarcinoma prostate."	Identified from the Human Clinical Data	High Expreesion	PSA decline rate	99.80%	%	.	.	.	.	.	.	.	.	2 cycles	8.0 MBq/cycle	.	"In view of refractory disease, the patient was administered 2 cycles of 225Ac-PSMA-617 (8.0 MBq/cycle) intravenously at 8 weeks intervals. Eight weeks following the second cycle, his serum PSA declined from 41.7 ng/mL to 0.1 ng/mL, and a repeat 68Ga-PSMA-11 PET/CT showed complete response."	"<sup>177</sup>Lu-PSMA-617 radioligand therapy (RLT) has evolved as a suitable alternative to existing therapeutic options in patients with metastatic castration-resistant prostate cancer. With the emergence of -emitters such as 225Ac, the efficacy of PSMA-RLT has further improved. Xerostomia and myelosuppression are common early treatment-emergent adverse events in patients receiving this therapy."
REF00211	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Biochemical response according to PCWG3 criteria	36%	%	.	.	.	64 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	Cumulative mean activity of 11.5 (8.1-14.9) GBq	.	"At restaging, 23 (36%) patients achieved a biochemical response according to PCWG3 criteria, while 41 patients (64%) patients were biochemical non-responders, 56% of which with a biochemical progression (n = 23). There were no therapy-related deaths documented in the observation period."	"In general, the first two cycles of PSMA-RLT were well tolerated haematologically. Qualitative and quantitative bone marrow impairment appears closely associated with osseous tumour burden as only patients with advanced bone involvement and non-response to therapy exhibited high-grade haematological adverse events as well as a significant mean decline of haematological parameters. This implies that in patients with already advanced mCRPC, non-response to PSMA-RLT may be a major cause of bone marrow impairment during early treatment cycles."
REF00211	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Biochemical non-response according to PCWG3 criteria	64%	%	.	.	.	64 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	Cumulative mean activity of 11.5 (8.1-14.9) GBq	.	"At restaging, 23 (36%) patients achieved a biochemical response according to PCWG3 criteria, while 41 patients (64%) patients were biochemical non-responders, 56% of which with a biochemical progression (n = 23). There were no therapy-related deaths documented in the observation period."	"In general, the first two cycles of PSMA-RLT were well tolerated haematologically. Qualitative and quantitative bone marrow impairment appears closely associated with osseous tumour burden as only patients with advanced bone involvement and non-response to therapy exhibited high-grade haematological adverse events as well as a significant mean decline of haematological parameters. This implies that in patients with already advanced mCRPC, non-response to PSMA-RLT may be a major cause of bone marrow impairment during early treatment cycles."
REF00211	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Biochemical progression according to PCWG3 criteria	56%	%	.	.	.	64 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	Cumulative mean activity of 11.5 (8.1-14.9) GBq	.	"At restaging, 23 (36%) patients achieved a biochemical response according to PCWG3 criteria, while 41 patients (64%) patients were biochemical non-responders, 56% of which with a biochemical progression (n = 23). There were no therapy-related deaths documented in the observation period."	"In general, the first two cycles of PSMA-RLT were well tolerated haematologically. Qualitative and quantitative bone marrow impairment appears closely associated with osseous tumour burden as only patients with advanced bone involvement and non-response to therapy exhibited high-grade haematological adverse events as well as a significant mean decline of haematological parameters. This implies that in patients with already advanced mCRPC, non-response to PSMA-RLT may be a major cause of bone marrow impairment during early treatment cycles."
REF00211	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 anaemia	8%	%	.	.	.	64 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	Cumulative mean activity of 11.5 (8.1-14.9) GBq	.	"In addition, lower grade thrombopenia and leukopenia were observed in 9 (14%) and 11 (17%) patients at baseline, respectively. During the observation period, severe (grade 3) anaemia, thrombopenia and leukopenia occurred in 5 (8%), 2 (3%) and 1 (2%) patients, all of whom suffered from disseminated or diffuse bone involvement according to promise criteria and none of whom experienced biochemical response over the course of therapy"	"In general, the first two cycles of PSMA-RLT were well tolerated haematologically. Qualitative and quantitative bone marrow impairment appears closely associated with osseous tumour burden as only patients with advanced bone involvement and non-response to therapy exhibited high-grade haematological adverse events as well as a significant mean decline of haematological parameters. This implies that in patients with already advanced mCRPC, non-response to PSMA-RLT may be a major cause of bone marrow impairment during early treatment cycles."
REF00211	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Thrombopenia	3%	%	.	.	.	64 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	Cumulative mean activity of 11.5 (8.1-14.9) GBq	.	"In addition, lower grade thrombopenia and leukopenia were observed in 9 (14%) and 11 (17%) patients at baseline, respectively. During the observation period, severe (grade 3) anaemia, thrombopenia and leukopenia occurred in 5 (8%), 2 (3%) and 1 (2%) patients, all of whom suffered from disseminated or diffuse bone involvement according to promise criteria and none of whom experienced biochemical response over the course of therapy"	"In general, the first two cycles of PSMA-RLT were well tolerated haematologically. Qualitative and quantitative bone marrow impairment appears closely associated with osseous tumour burden as only patients with advanced bone involvement and non-response to therapy exhibited high-grade haematological adverse events as well as a significant mean decline of haematological parameters. This implies that in patients with already advanced mCRPC, non-response to PSMA-RLT may be a major cause of bone marrow impairment during early treatment cycles."
REF00211	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Leukopenia	2%	%	.	.	.	64 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	Cumulative mean activity of 11.5 (8.1-14.9) GBq	.	"In addition, lower grade thrombopenia and leukopenia were observed in 9 (14%) and 11 (17%) patients at baseline, respectively. During the observation period, severe (grade 3) anaemia, thrombopenia and leukopenia occurred in 5 (8%), 2 (3%) and 1 (2%) patients, all of whom suffered from disseminated or diffuse bone involvement according to promise criteria and none of whom experienced biochemical response over the course of therapy"	"In general, the first two cycles of PSMA-RLT were well tolerated haematologically. Qualitative and quantitative bone marrow impairment appears closely associated with osseous tumour burden as only patients with advanced bone involvement and non-response to therapy exhibited high-grade haematological adverse events as well as a significant mean decline of haematological parameters. This implies that in patients with already advanced mCRPC, non-response to PSMA-RLT may be a major cause of bone marrow impairment during early treatment cycles."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	"Bone marrow, liver or renal toxicity rate"	65.38%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Bone marrow toxicity	58.77%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge; 2 thrombocytopenia	25.28%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge; 3 thrombocytopenia	8.91%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 anemia	7.29%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 leucopenia	7.53%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 lymphocytopenia	48.01%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 neutropenia	3.74%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Rate of liver toxicity	14.58%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 aspartate aminotransferase	2.53%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Alanine aminotransferase grade &ge;3	3.02%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Alkaline phosphatase grade &ge;3	3.54%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 bilirubin	1.39%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Albumin grade &ge;3	0.23%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Kidney toxicity	7.34%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 Creatinine	0%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Creatinine increase &ge;40%	5.26%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Creatinine	3.93%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Creatinine	2.29%	%	.	.	.	439 female patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (22.2-29.6 GBq) (800 mCi [600-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	"Bone marrow, liver or renal toxicity rate"	60.86%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Bone marrow toxicity	56.01%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge; 2 thrombocytopenia	17.67%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge; 3 thrombocytopenia	6.19%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 anemia	3.00%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 leucopenia	5.63%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 lymphocytopenia	48.85%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 neutropenia	2.84%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Rate of liver toxicity	10.49%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 aspartate aminotransferase	1.51%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Alanine aminotransferase grade &ge;3	1.50%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Alkaline phosphatase grade &ge;3	2.31%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 bilirubin	0.76%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Albumin grade &ge;3	0.19%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Kidney toxicity	5.06%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 Creatinine	0.37%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Creatinine increase &ge;40%	3.75%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Creatinine	2.46%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00212	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Creatinine	1.13%	%	.	.	.	534 male patients with neuroendocrine tumour.	.	.	.	.	Median of 4 cycles	Cumulative administered activity 29.6 GBq (25.9-29.6 GBq) (800 mCi [700-800 mCi])	.	"Grade 2, 3, or 4 thrombocytopenia occurred more often in women (25%) than in men (18%, P = 0.004), which was driven by a significant increase in grade &ge;3 thrombocytopenia in women (11% vs 6%, P = 0.008). Grade &ge;3 anemia was likewise more prevalent in women (7%) than in men (3%, P = 0.002). A &ge; 25% decrease from the baseline hemoglobin level occurred in 55 women (13%) and 38 men (7%) (P = 0.004). Of the patients with grade &ge;3 anemia, 21 (66%) female and 10 (63%) male patients also developed grade &ge;2 thrombocytopenia (P = 0.831). Grade &ge;3 pancytopenia (thrombocytopenia, leukopenia, and anemia) occurred in 1% of both sexes. Of all study patients, 52 female patients (12%) and 47 male patients (9%) received a cumulative activity of <27.8 GBq (750 mCi) as a result of a bone marrow DLT (P = 0.122)."	"Subacute PRRT-related toxicities are commonly detected and can lead to dose adjustments, treatment delay, and treatment discontinuation in a limited number of patients. Severe platelet and hemoglobin toxicities were more frequently observed in female than male NET patients, without evidently leading to a lower cumulative <sup>177</sup>Lu-DOTATATE activity. Future research should focus on the etiology and on the impact on the treatment efficacy and long-term safety of PRRT between sexes."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	White blood cells count	8x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	120 MBq	.	"There were no significant differences in blood values in control animals at the different time points during the experiment; hence, data for all control animals (a mean from the different time points of each individual animal) are presented at all timepoints. Already after 4 days post injection of 160 MBq <sup>177</sup>Lu-PSMA-617, there was a significant lowering of WBC, notably in lymphocytes but not in monocytes and granulocytes. The drop in WBC was significant in all groups receiving activity, 120, 160, and 200 MBq, after 13 days, where monocytes and granulocytes, in addition to lymphocytes (with an exception for 120 MBq), also were significantly lower than the control group."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	White blood cells count	6x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	160 MBq	.	"There were no significant differences in blood values in control animals at the different time points during the experiment; hence, data for all control animals (a mean from the different time points of each individual animal) are presented at all timepoints. Already after 4 days post injection of 160 MBq <sup>177</sup>Lu-PSMA-617, there was a significant lowering of WBC, notably in lymphocytes but not in monocytes and granulocytes. The drop in WBC was significant in all groups receiving activity, 120, 160, and 200 MBq, after 13 days, where monocytes and granulocytes, in addition to lymphocytes (with an exception for 120 MBq), also were significantly lower than the control group."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	White blood cells count	6x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	120 MBq	.	"There were no significant differences in blood values in control animals at the different time points during the experiment; hence, data for all control animals (a mean from the different time points of each individual animal) are presented at all timepoints. Already after 4 days post injection of 160 MBq <sup>177</sup>Lu-PSMA-617, there was a significant lowering of WBC, notably in lymphocytes but not in monocytes and granulocytes. The drop in WBC was significant in all groups receiving activity, 120, 160, and 200 MBq, after 13 days, where monocytes and granulocytes, in addition to lymphocytes (with an exception for 120 MBq), also were significantly lower than the control group."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	White blood cells count	8x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	160 MBq	.	"There were no significant differences in blood values in control animals at the different time points during the experiment; hence, data for all control animals (a mean from the different time points of each individual animal) are presented at all timepoints. Already after 4 days post injection of 160 MBq <sup>177</sup>Lu-PSMA-617, there was a significant lowering of WBC, notably in lymphocytes but not in monocytes and granulocytes. The drop in WBC was significant in all groups receiving activity, 120, 160, and 200 MBq, after 13 days, where monocytes and granulocytes, in addition to lymphocytes (with an exception for 120 MBq), also were significantly lower than the control group."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	White blood cells count	7x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	200 MBq	.	"There were no significant differences in blood values in control animals at the different time points during the experiment; hence, data for all control animals (a mean from the different time points of each individual animal) are presented at all timepoints. Already after 4 days post injection of 160 MBq <sup>177</sup>Lu-PSMA-617, there was a significant lowering of WBC, notably in lymphocytes but not in monocytes and granulocytes. The drop in WBC was significant in all groups receiving activity, 120, 160, and 200 MBq, after 13 days, where monocytes and granulocytes, in addition to lymphocytes (with an exception for 120 MBq), also were significantly lower than the control group."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Lymphocyte count	5.5x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	120 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Lymphocyte count	4x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	160 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Lymphocyte count	4.5x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	200 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Lymphocyte count	7x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	160 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Lymphocyte count	6.5x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	200 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Monocyte count	0.6x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	120 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Monocyte count	0.35x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	160 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Monocyte count	0.5x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	200 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Monocyte count	0.2x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	120 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Monocyte count	0.45x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	160 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Monocyte count	0.3x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	200 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Granulocyte count	2.2x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	120 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Granulocyte count	1.9x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	160 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Granulocyte count	2.1x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	200 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Granulocyte count	1.2x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	120 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Granulocyte count	1.5x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	160 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Granulocyte count	1.3x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	200 MBq	.	"After 17 days, the 160 MBq group still had lower WBC and lymphocytes, but the monocytes and granulocytes had recovered to a similar level as control animals. At 21, 25, and 32 days, there were no significant differences between control and animals receiving <sup>177</sup>Lu-PSMA-617, suggesting no long-lasting hematotoxicity. Overall, there was no correlation between activity received and decrease in white blood cells at the different time points, not when correcting for body mass differences either."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Red blood cells count	8x10<sup>12</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	120 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Red blood cells count	9x10<sup>12</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	160 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Red blood cells count	8.5x10<sup>12</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	200 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Red blood cells count	3x10<sup>12</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	120 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Red blood cells count	2x10<sup>12</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	160 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Red blood cells count	2.5x10<sup>12</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	200 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Mean cell volume	56.5x10<sup>12</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	120 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Mean cell volume	55.8x10<sup>12</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	160 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Mean cell volume	55.5x10<sup>12</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	200 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Mean cell volume	1x10<sup>12</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	120 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Mean cell volume	0.3x10<sup>12</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	13 days	160 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Mean cell volume	57x10<sup>12</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	17 days	160 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Mean cell volume	1.5x10<sup>12</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	17 days	160 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Hemoglobin	12 g/dL	g/dL	.	.	.	.	.	.	.	.	21 days	120 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Hemoglobin	12 g/dL	g/dL	.	.	.	.	.	.	.	.	21 days	160 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Hemoglobin	13.5 g/dL	g/dL	.	.	.	.	.	.	.	.	21 days	200 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Hemoglobin decrease	4 g/dL	g/dL	.	.	.	.	.	.	.	.	21 days	120 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Hemoglobin decrease	4 g/dL	g/dL	.	.	.	.	.	.	.	.	21 days	160 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Hemoglobin decrease	2.5 g/dL	g/dL	.	.	.	.	.	.	.	.	21 days	200 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Hematocrit decrease rate	43%	%	.	.	.	.	.	.	.	.	21 days	120 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Hematocrit decrease rate	40%	%	.	.	.	.	.	.	.	.	21 days	160 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Hematocrit decrease rate	49%	%	.	.	.	.	.	.	.	.	21 days	200 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Hematocrit decrease rate	16%	%	.	.	.	.	.	.	.	.	21 days	120 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Hematocrit decrease rate	19%	%	.	.	.	.	.	.	.	.	21 days	160 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Hematocrit decrease rate	10%	%	.	.	.	.	.	.	.	.	21 days	200 MBq	.	"After 21 days, all groups showed a tendency toward a lower number of RBCs, although only significant in the 120 MBq group. However, when analyzing the blood at 25 days post injection, the number of RBCs and HCT were again significantly lower in the 160 MBq animals. After 32 days, all studied parameters involving RBCs were normalized and did not differ from control mice, with the only exception of MCV in the 200 MBq group. Similar to the RBCs, the spread, in general, was larger in the treated groups for MCV, HBG, and HCT than in the control group. Further, as with the WBC, the decrease in RBCs and HBG levels did not have a correlation to injected activity, and no significant differences between the 120, 160, and 200 MBq were seen at any time point."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Platelet count	120x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	21 days	120 MBq	.	"After 17 days, a significant drop in platelet levels could be seen in the 160 MBq group, which remained significantly lower compared to the control group after 21 days. This was also seen for the 120 MBq group, but not in the 200 MBq group, although there was a large spread in the latter group. The reduction in platelet count was still significant after 25 days in the 160 MBq group. At the last time point, 32 days, animals that had received activity had a large interval in the number of platelets, but at the group level, there was no difference compared to the control group."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Platelet count	75x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	21 days	160 MBq	.	"After 17 days, a significant drop in platelet levels could be seen in the 160 MBq group, which remained significantly lower compared to the control group after 21 days. This was also seen for the 120 MBq group, but not in the 200 MBq group, although there was a large spread in the latter group. The reduction in platelet count was still significant after 25 days in the 160 MBq group. At the last time point, 32 days, animals that had received activity had a large interval in the number of platelets, but at the group level, there was no difference compared to the control group."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Platelet count	250x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	21 days	200 MBq	.	"After 17 days, a significant drop in platelet levels could be seen in the 160 MBq group, which remained significantly lower compared to the control group after 21 days. This was also seen for the 120 MBq group, but not in the 200 MBq group, although there was a large spread in the latter group. The reduction in platelet count was still significant after 25 days in the 160 MBq group. At the last time point, 32 days, animals that had received activity had a large interval in the number of platelets, but at the group level, there was no difference compared to the control group."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Platelet count	180x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	21 days	120 MBq	.	"After 17 days, a significant drop in platelet levels could be seen in the 160 MBq group, which remained significantly lower compared to the control group after 21 days. This was also seen for the 120 MBq group, but not in the 200 MBq group, although there was a large spread in the latter group. The reduction in platelet count was still significant after 25 days in the 160 MBq group. At the last time point, 32 days, animals that had received activity had a large interval in the number of platelets, but at the group level, there was no difference compared to the control group."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Platelet count	225x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	21 days	160 MBq	.	"After 17 days, a significant drop in platelet levels could be seen in the 160 MBq group, which remained significantly lower compared to the control group after 21 days. This was also seen for the 120 MBq group, but not in the 200 MBq group, although there was a large spread in the latter group. The reduction in platelet count was still significant after 25 days in the 160 MBq group. At the last time point, 32 days, animals that had received activity had a large interval in the number of platelets, but at the group level, there was no difference compared to the control group."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Platelet count	50x10<sup>9</sup>/L	L<sup>-1</sup>	.	.	.	.	.	.	.	.	4 days	200 MBq	.	"After 17 days, a significant drop in platelet levels could be seen in the 160 MBq group, which remained significantly lower compared to the control group after 21 days. This was also seen for the 120 MBq group, but not in the 200 MBq group, although there was a large spread in the latter group. The reduction in platelet count was still significant after 25 days in the 160 MBq group. At the last time point, 32 days, animals that had received activity had a large interval in the number of platelets, but at the group level, there was no difference compared to the control group."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Body mass decrease	0.55 g	g	.	.	.	.	.	.	.	.	4 days	120 MBq	.	"Body mass was continuously monitored to assess health. Although mice receiving activity had an initial significant body mass loss (presented as gained/lost fraction from starting body mass), all mice had gained additional body mass at the end of the experiment. There was no significant difference in the body mass gains between groups (presented as gained mass relative to starting body mass)."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Body mass decrease	0.6 g	g	.	.	.	.	.	.	.	.	4 days	160 MBq	.	"Body mass was continuously monitored to assess health. Although mice receiving activity had an initial significant body mass loss (presented as gained/lost fraction from starting body mass), all mice had gained additional body mass at the end of the experiment. There was no significant difference in the body mass gains between groups (presented as gained mass relative to starting body mass)."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00214	PDC_00029	Metastatic castration-resistant prostate cancer	BALB/cAnNRj mice.	Obtained from the Model Organism Data	High Expreesion	Body mass decrease	0.55 g	g	.	.	.	.	.	.	.	.	4 days	200 MBq	.	"Body mass was continuously monitored to assess health. Although mice receiving activity had an initial significant body mass loss (presented as gained/lost fraction from starting body mass), all mice had gained additional body mass at the end of the experiment. There was no significant difference in the body mass gains between groups (presented as gained mass relative to starting body mass)."	"In conclusion, the hematotoxicity resulting from the infusion of radioactivity doses up to 200 MBq in our mouse model is transient, and mice exhibit normalized blood values within a month with no other apparent adverse effects (e.g., deaths, bleeding, or sustained body mass loss). These activities in animal models may increase the relevance when studying renal toxicity in animal models and, hence, help improve therapeutic translation from animal models to the clinic."
REF00216	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	42.90%	%	.	.	.	"7 patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive neuroendocrine tumours."	.	.	.	.	4 cycles	21.3-30.1 GBq total dose	.	"Grade 3 thrombocytopenia occurred in one patient, but no other grade 3 or 4 major hematologic or renal toxicity was observed. The best objective response to SNU-KB-01 was partial response. Overall response rate was 42.9% and disease control rate was 85.7%."	"In conclusion, for the first time in Korea, we have conducted a clinical trial of PRRT with SNU-KB-01, a NCA <sup>177</sup>Lu-DOTATATE, in patients with SSTR-positive NET. Treatment with SNU-KB-01 was safe and resulted in control of disease in most of the patients with high SSTR expression. The recommended dose per cycle of SNU-KB-01 was determined to be 7.40 GBq for the phase 2 trial. Our results indicate SNU-KB-01 as a potentially safe and efficacious treatment option for NET patients and are expected to provide a wider choice of treatment opportunities for patients with various types of SSTR-positive tumors in Korea."
REF00216	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	85.70%	%	.	.	.	"7 patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive neuroendocrine tumours."	.	.	.	.	4 cycles	21.3-30.1 GBq total dose	.	"Grade 3 thrombocytopenia occurred in one patient, but no other grade 3 or 4 major hematologic or renal toxicity was observed. The best objective response to SNU-KB-01 was partial response. Overall response rate was 42.9% and disease control rate was 85.7%."	"In conclusion, for the first time in Korea, we have conducted a clinical trial of PRRT with SNU-KB-01, a NCA <sup>177</sup>Lu-DOTATATE, in patients with SSTR-positive NET. Treatment with SNU-KB-01 was safe and resulted in control of disease in most of the patients with high SSTR expression. The recommended dose per cycle of SNU-KB-01 was determined to be 7.40 GBq for the phase 2 trial. Our results indicate SNU-KB-01 as a potentially safe and efficacious treatment option for NET patients and are expected to provide a wider choice of treatment opportunities for patients with various types of SSTR-positive tumors in Korea."
REF00216	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	14.30%	%	.	.	.	"7 patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive neuroendocrine tumours."	.	.	.	.	4 cycles	21.3-30.1 GBq total dose	.	"Among seven patients, the best objective response to SNU-KB-01 was the PR observed in three patients (42.9%). No CR was observed. Three patients (42.9%) had SD and one patient (14.3%) had PD. The ORR (CR+PR) was 42.9%, and the DCR (CR+PR+SD) was 85.7%."	"In conclusion, for the first time in Korea, we have conducted a clinical trial of PRRT with SNU-KB-01, a NCA <sup>177</sup>Lu-DOTATATE, in patients with SSTR-positive NET. Treatment with SNU-KB-01 was safe and resulted in control of disease in most of the patients with high SSTR expression. The recommended dose per cycle of SNU-KB-01 was determined to be 7.40 GBq for the phase 2 trial. Our results indicate SNU-KB-01 as a potentially safe and efficacious treatment option for NET patients and are expected to provide a wider choice of treatment opportunities for patients with various types of SSTR-positive tumors in Korea."
REF00216	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	42.90%	%	.	.	.	"7 patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive neuroendocrine tumours."	.	.	.	.	4 cycles	21.3-30.1 GBq total dose	.	"Among seven patients, the best objective response to SNU-KB-01 was the PR observed in three patients (42.9%). No CR was observed. Three patients (42.9%) had SD and one patient (14.3%) had PD. The ORR (CR+PR) was 42.9%, and the DCR (CR+PR+SD) was 85.7%."	"In conclusion, for the first time in Korea, we have conducted a clinical trial of PRRT with SNU-KB-01, a NCA <sup>177</sup>Lu-DOTATATE, in patients with SSTR-positive NET. Treatment with SNU-KB-01 was safe and resulted in control of disease in most of the patients with high SSTR expression. The recommended dose per cycle of SNU-KB-01 was determined to be 7.40 GBq for the phase 2 trial. Our results indicate SNU-KB-01 as a potentially safe and efficacious treatment option for NET patients and are expected to provide a wider choice of treatment opportunities for patients with various types of SSTR-positive tumors in Korea."
REF00216	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 thrombocytopenia	14.30%	%	.	.	.	"7 patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive neuroendocrine tumours."	.	.	.	.	4 cycles	21.3-30.1 GBq total dose	.	"There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles."	"In conclusion, for the first time in Korea, we have conducted a clinical trial of PRRT with SNU-KB-01, a NCA <sup>177</sup>Lu-DOTATATE, in patients with SSTR-positive NET. Treatment with SNU-KB-01 was safe and resulted in control of disease in most of the patients with high SSTR expression. The recommended dose per cycle of SNU-KB-01 was determined to be 7.40 GBq for the phase 2 trial. Our results indicate SNU-KB-01 as a potentially safe and efficacious treatment option for NET patients and are expected to provide a wider choice of treatment opportunities for patients with various types of SSTR-positive tumors in Korea."
REF00216	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 anemia	28.60%	%	.	.	.	"7 patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive neuroendocrine tumours."	.	.	.	.	4 cycles	21.3-30.1 GBq total dose	.	"There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles."	"In conclusion, for the first time in Korea, we have conducted a clinical trial of PRRT with SNU-KB-01, a NCA <sup>177</sup>Lu-DOTATATE, in patients with SSTR-positive NET. Treatment with SNU-KB-01 was safe and resulted in control of disease in most of the patients with high SSTR expression. The recommended dose per cycle of SNU-KB-01 was determined to be 7.40 GBq for the phase 2 trial. Our results indicate SNU-KB-01 as a potentially safe and efficacious treatment option for NET patients and are expected to provide a wider choice of treatment opportunities for patients with various types of SSTR-positive tumors in Korea."
REF00216	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 thrombocytopenia	57.10%	%	.	.	.	"7 patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive neuroendocrine tumours."	.	.	.	.	4 cycles	21.3-30.1 GBq total dose	.	"There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles."	"In conclusion, for the first time in Korea, we have conducted a clinical trial of PRRT with SNU-KB-01, a NCA <sup>177</sup>Lu-DOTATATE, in patients with SSTR-positive NET. Treatment with SNU-KB-01 was safe and resulted in control of disease in most of the patients with high SSTR expression. The recommended dose per cycle of SNU-KB-01 was determined to be 7.40 GBq for the phase 2 trial. Our results indicate SNU-KB-01 as a potentially safe and efficacious treatment option for NET patients and are expected to provide a wider choice of treatment opportunities for patients with various types of SSTR-positive tumors in Korea."
REF00216	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 leukopenia	71.40%	%	.	.	.	"7 patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive neuroendocrine tumours."	.	.	.	.	4 cycles	21.3-30.1 GBq total dose	.	"There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles."	"In conclusion, for the first time in Korea, we have conducted a clinical trial of PRRT with SNU-KB-01, a NCA <sup>177</sup>Lu-DOTATATE, in patients with SSTR-positive NET. Treatment with SNU-KB-01 was safe and resulted in control of disease in most of the patients with high SSTR expression. The recommended dose per cycle of SNU-KB-01 was determined to be 7.40 GBq for the phase 2 trial. Our results indicate SNU-KB-01 as a potentially safe and efficacious treatment option for NET patients and are expected to provide a wider choice of treatment opportunities for patients with various types of SSTR-positive tumors in Korea."
REF00216	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 neutropenia	42.90%	%	.	.	.	"7 patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive neuroendocrine tumours."	.	.	.	.	4 cycles	21.3-30.1 GBq total dose	.	"There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles."	"In conclusion, for the first time in Korea, we have conducted a clinical trial of PRRT with SNU-KB-01, a NCA <sup>177</sup>Lu-DOTATATE, in patients with SSTR-positive NET. Treatment with SNU-KB-01 was safe and resulted in control of disease in most of the patients with high SSTR expression. The recommended dose per cycle of SNU-KB-01 was determined to be 7.40 GBq for the phase 2 trial. Our results indicate SNU-KB-01 as a potentially safe and efficacious treatment option for NET patients and are expected to provide a wider choice of treatment opportunities for patients with various types of SSTR-positive tumors in Korea."
REF00216	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 renal toxicity	14.30%	%	.	.	.	"7 patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive neuroendocrine tumours."	.	.	.	.	4 cycles	21.3-30.1 GBq total dose	.	"There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles."	"In conclusion, for the first time in Korea, we have conducted a clinical trial of PRRT with SNU-KB-01, a NCA <sup>177</sup>Lu-DOTATATE, in patients with SSTR-positive NET. Treatment with SNU-KB-01 was safe and resulted in control of disease in most of the patients with high SSTR expression. The recommended dose per cycle of SNU-KB-01 was determined to be 7.40 GBq for the phase 2 trial. Our results indicate SNU-KB-01 as a potentially safe and efficacious treatment option for NET patients and are expected to provide a wider choice of treatment opportunities for patients with various types of SSTR-positive tumors in Korea."
REF00216	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 hepatotoxicities	28.60%	%	.	.	.	"7 patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive neuroendocrine tumours."	.	.	.	.	4 cycles	21.3-30.1 GBq total dose	.	"There was grade 3 thrombocytopenia in one patient (14.3%), but no other grade 3 or 4 major hematologic, renal, hepatotoxicity was observed. Grade 1 or 2 hematologic toxicities were anemia (28.6%), thrombocytopenia (57.1%), leukopenia (71.4%), and neutropenia (42.9%). Grade 1 renal toxicity occurred in one patient (14.3%). Grade 1 or 2 hepatotoxicities were observed in two patients (28.6%). The trend of the progressive decline of hematological parameters was observed during the treatment cycles."	"In conclusion, for the first time in Korea, we have conducted a clinical trial of PRRT with SNU-KB-01, a NCA <sup>177</sup>Lu-DOTATATE, in patients with SSTR-positive NET. Treatment with SNU-KB-01 was safe and resulted in control of disease in most of the patients with high SSTR expression. The recommended dose per cycle of SNU-KB-01 was determined to be 7.40 GBq for the phase 2 trial. Our results indicate SNU-KB-01 as a potentially safe and efficacious treatment option for NET patients and are expected to provide a wider choice of treatment opportunities for patients with various types of SSTR-positive tumors in Korea."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	15.3 months	months	NCT03511664	The primary objective of this study was to compare the two alternate primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) in patients with progressive prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who received 177Lu-PSMA-617 in addition to best supportive/best standard of care (BSC/BSoC) versus patients treated with best supportive/best standard of care alone.	Phase 3	551 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	6 doses every 6 weeks plus bsoc	7.4 GBq	.	Median OS was significantly longer with lutetium Lu 177 vipivotide tetraxetan plus BSoC (n = 551) than with BSoC alone (n = 280) [15.3 vs 11.3 months [HR 0.62 (95% CI 0.52-0.74); p < 0.001]. Median rPFS was 8.7 months in the lutetium Lu 177 vipivotide tetraxetan plus BSoC arm (n = 385) compared with 3.4 months in the BSoC alone arm (n = 196) [HR for progression or death 0.40 (99.2% CI 0.29-0.57); p < 0.001). The overall response rate was also significantly higher in lutetium Lu 177 vipivotide tetraxetan arm (n = 319 patients with evaluable disease at baseline) than in the BSoC alone arm (n = 120) [30% vs 2%; p < 0.001].	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median radiographic progression-free survival (rPFS)	8.7 months	months	NCT03511664	The primary objective of this study was to compare the two alternate primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) in patients with progressive prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who received 177Lu-PSMA-617 in addition to best supportive/best standard of care (BSC/BSoC) versus patients treated with best supportive/best standard of care alone.	Phase 3	551 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	6 doses every 6 weeks plus bsoc	7.4 GBq	.	Median OS was significantly longer with lutetium Lu 177 vipivotide tetraxetan plus BSoC (n = 551) than with BSoC alone (n = 280) [15.3 vs 11.3 months [HR 0.62 (95% CI 0.52-0.74); p < 0.001]. Median rPFS was 8.7 months in the lutetium Lu 177 vipivotide tetraxetan plus BSoC arm (n = 385) compared with 3.4 months in the BSoC alone arm (n = 196) [HR for progression or death 0.40 (99.2% CI 0.29-0.57); p < 0.001). The overall response rate was also significantly higher in lutetium Lu 177 vipivotide tetraxetan arm (n = 319 patients with evaluable disease at baseline) than in the BSoC alone arm (n = 120) [30% vs 2%; p < 0.001].	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	30%	%	NCT03511664	The primary objective of this study was to compare the two alternate primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) in patients with progressive prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who received 177Lu-PSMA-617 in addition to best supportive/best standard of care (BSC/BSoC) versus patients treated with best supportive/best standard of care alone.	Phase 3	319 patients with metastatic castration-resistant prostate cancer and evaluable disease at baseline.	.	.	41.6 h	.	6 doses every 6 weeks plus bsoc	7.4 GBq	.	Median OS was significantly longer with lutetium Lu 177 vipivotide tetraxetan plus BSoC (n = 551) than with BSoC alone (n = 280) [15.3 vs 11.3 months [HR 0.62 (95% CI 0.52-0.74); p < 0.001]. Median rPFS was 8.7 months in the lutetium Lu 177 vipivotide tetraxetan plus BSoC arm (n = 385) compared with 3.4 months in the BSoC alone arm (n = 196) [HR for progression or death 0.40 (99.2% CI 0.29-0.57); p < 0.001). The overall response rate was also significantly higher in lutetium Lu 177 vipivotide tetraxetan arm (n = 319 patients with evaluable disease at baseline) than in the BSoC alone arm (n = 120) [30% vs 2%; p < 0.001].	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	14 months	months	NCT03042312	"This was an open-label, multicenter, prospective trial to assess safety and efficacy of 177Lu-PSMA-617 in patients with metastatic castration resistant prostate cancer."	Phase 2	43 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	4 cycles	6.0/7.4 GBq	.	"Treatment with lutetium Lu 177 vipivotide tetraxetan was associated with a median OS of 14 months in the RESIST-PC trial (NCT03042312). Eligible patients had progressive mCRPC after treatment with AR pathway inhibition, were either chemotherapy nave or were post chemotherapy and had sufficient PSMA expression by PSMA PET and were randomized to receive up to 4 cycles of lutetium Lu 177 vipivotide tetraxetan 6.0 or 7.4 GBq. The trial was terminated early because of sponsorship transfer; data are from 43 patients the US arm of the trial."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	64.00%	%	ACTRN12615000912583	"Background: Lutetium-177 (177Lu)-PSMA-617 (LuPSMA) is a radiolabelled small molecule that binds with high affinity to prostate specific membrane antigen (PSMA) enabling targeted delivery of beta-radiation. We have previously reported favourable activity with low toxicity in a 30 patient study in men with metastatic castrate-resistant prostate cancer (mCRPC) and now report updated results including a twenty patient extension cohort. Methods: In this phase II trial, 50 patients with PSMA-avid mCRPC who had progressed after standard therapies received up to 4 cycles of LuPSMA every 6 weeks. The primary endpoints were PSA response (PCWG2) and toxicity (CTCAE v4). Other endpoints included imaging response, PSA PFS and OS. Cut-off for analysis 5 Oct 2018. Results: 76 men were screened to identify 50 patients eligible for treatment. Median PSA doubling time was 2.6 months. The majority of patients had received prior docetaxel (84%), cabazitaxel (48%), and abiraterone and/or enzalutamide (90%). The mean administered radioactivity was 7.5 GBq/cycle. PSA decline 50% was achieved in 32 of 50 patients (64%, 95% CI 50-77%), including 22 patients (44%, 95% CI 30-59%) with a PSA decline 80%. 27 patients had measurable soft tissue at baseline and 56% of these patients had a partial or complete response by RECIST 1.1. The most common toxicities attributed to LuPSMA were transient G1-2 dry mouth in 68%, G1-2 nausea in 48%, and G1-2 fatigue in 36%. G3-4 toxicities attributed to LuPSMA were infrequent with thrombocytopenia in 10% and anaemia in 10%. Median PSA PFS was 6.9 months (95% CI 6.0-8.7) and median OS was 13.3 months (95% CI 10.5-18.0). Upon subsequent progression, further LuPSMA was administered to 14 patients (median 2 cycles commencing 359 days from enrolment); PSA 50% response occurred in 9 patients (64%). Conclusions: This expanded 50 patient cohort confirms high response rates and low toxicity with LuPSMA in men who had progressed after standard therapies. In patients who subsequently progressed and were administered further LuPSMA, high response rates were also observed. These results have provided the basis for randomised controlled trials currently underway."	Phase 2	"50 patients with progressive, PSMA-positive, symptomatic metastatic castration-resistant prostate cancer."	.	.	41.6 h	.	4 cycles every 6 weeks	7.5 GBq (range 4-8.9 GBq)	.	"A PSA response (PSA reduction of &ge; 50% from baseline) was seen in 32 of 50 patients (64%) with progressive, PSMA-positive, symptomatic mCRPC who received up to 4 cycles of lutetium Lu 177 vipivotide tetraxetan every 6 weeks in the LuPSMA study (ACTRN12615000912583). 22 of 50 patients (44%) had a &ge; 80% decrease in PSA. At a median follow-up of 31.4 months, median OS was 13.3 months in the overall population and 18.4 months in those achieving a PSA response."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	44.00%	%	ACTRN12615000912583	"Background: Lutetium-177 (177Lu)-PSMA-617 (LuPSMA) is a radiolabelled small molecule that binds with high affinity to prostate specific membrane antigen (PSMA) enabling targeted delivery of beta-radiation. We have previously reported favourable activity with low toxicity in a 30 patient study in men with metastatic castrate-resistant prostate cancer (mCRPC) and now report updated results including a twenty patient extension cohort. Methods: In this phase II trial, 50 patients with PSMA-avid mCRPC who had progressed after standard therapies received up to 4 cycles of LuPSMA every 6 weeks. The primary endpoints were PSA response (PCWG2) and toxicity (CTCAE v4). Other endpoints included imaging response, PSA PFS and OS. Cut-off for analysis 5 Oct 2018. Results: 76 men were screened to identify 50 patients eligible for treatment. Median PSA doubling time was 2.6 months. The majority of patients had received prior docetaxel (84%), cabazitaxel (48%), and abiraterone and/or enzalutamide (90%). The mean administered radioactivity was 7.5 GBq/cycle. PSA decline 50% was achieved in 32 of 50 patients (64%, 95% CI 50-77%), including 22 patients (44%, 95% CI 30-59%) with a PSA decline 80%. 27 patients had measurable soft tissue at baseline and 56% of these patients had a partial or complete response by RECIST 1.1. The most common toxicities attributed to LuPSMA were transient G1-2 dry mouth in 68%, G1-2 nausea in 48%, and G1-2 fatigue in 36%. G3-4 toxicities attributed to LuPSMA were infrequent with thrombocytopenia in 10% and anaemia in 10%. Median PSA PFS was 6.9 months (95% CI 6.0-8.7) and median OS was 13.3 months (95% CI 10.5-18.0). Upon subsequent progression, further LuPSMA was administered to 14 patients (median 2 cycles commencing 359 days from enrolment); PSA 50% response occurred in 9 patients (64%). Conclusions: This expanded 50 patient cohort confirms high response rates and low toxicity with LuPSMA in men who had progressed after standard therapies. In patients who subsequently progressed and were administered further LuPSMA, high response rates were also observed. These results have provided the basis for randomised controlled trials currently underway."	Phase 2	"50 patients with progressive, PSMA-positive, symptomatic metastatic castration-resistant prostate cancer."	.	.	41.6 h	.	4 cycles every 6 weeks	7.5 GBq (range 4-8.9 GBq)	.	"A PSA response (PSA reduction of &ge; 50% from baseline) was seen in 32 of 50 patients (64%) with progressive, PSMA-positive, symptomatic mCRPC who received up to 4 cycles of lutetium Lu 177 vipivotide tetraxetan every 6 weeks in the LuPSMA study (ACTRN12615000912583). 22 of 50 patients (44%) had a &ge; 80% decrease in PSA. At a median follow-up of 31.4 months, median OS was 13.3 months in the overall population and 18.4 months in those achieving a PSA response."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	13.3 months	months	ACTRN12615000912583	"Background: Lutetium-177 (177Lu)-PSMA-617 (LuPSMA) is a radiolabelled small molecule that binds with high affinity to prostate specific membrane antigen (PSMA) enabling targeted delivery of beta-radiation. We have previously reported favourable activity with low toxicity in a 30 patient study in men with metastatic castrate-resistant prostate cancer (mCRPC) and now report updated results including a twenty patient extension cohort. Methods: In this phase II trial, 50 patients with PSMA-avid mCRPC who had progressed after standard therapies received up to 4 cycles of LuPSMA every 6 weeks. The primary endpoints were PSA response (PCWG2) and toxicity (CTCAE v4). Other endpoints included imaging response, PSA PFS and OS. Cut-off for analysis 5 Oct 2018. Results: 76 men were screened to identify 50 patients eligible for treatment. Median PSA doubling time was 2.6 months. The majority of patients had received prior docetaxel (84%), cabazitaxel (48%), and abiraterone and/or enzalutamide (90%). The mean administered radioactivity was 7.5 GBq/cycle. PSA decline 50% was achieved in 32 of 50 patients (64%, 95% CI 50-77%), including 22 patients (44%, 95% CI 30-59%) with a PSA decline 80%. 27 patients had measurable soft tissue at baseline and 56% of these patients had a partial or complete response by RECIST 1.1. The most common toxicities attributed to LuPSMA were transient G1-2 dry mouth in 68%, G1-2 nausea in 48%, and G1-2 fatigue in 36%. G3-4 toxicities attributed to LuPSMA were infrequent with thrombocytopenia in 10% and anaemia in 10%. Median PSA PFS was 6.9 months (95% CI 6.0-8.7) and median OS was 13.3 months (95% CI 10.5-18.0). Upon subsequent progression, further LuPSMA was administered to 14 patients (median 2 cycles commencing 359 days from enrolment); PSA 50% response occurred in 9 patients (64%). Conclusions: This expanded 50 patient cohort confirms high response rates and low toxicity with LuPSMA in men who had progressed after standard therapies. In patients who subsequently progressed and were administered further LuPSMA, high response rates were also observed. These results have provided the basis for randomised controlled trials currently underway."	Phase 2	"50 patients with progressive, PSMA-positive, symptomatic metastatic castration-resistant prostate cancer."	.	.	41.6 h	.	4 cycles every 6 weeks	7.5 GBq (range 4-8.9 GBq)	.	"A PSA response (PSA reduction of &ge; 50% from baseline) was seen in 32 of 50 patients (64%) with progressive, PSMA-positive, symptomatic mCRPC who received up to 4 cycles of lutetium Lu 177 vipivotide tetraxetan every 6 weeks in the LuPSMA study (ACTRN12615000912583). 22 of 50 patients (44%) had a &ge; 80% decrease in PSA. At a median follow-up of 31.4 months, median OS was 13.3 months in the overall population and 18.4 months in those achieving a PSA response."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	"PSMA-expressing, low volume (&ge; 1 but &le; 1010 positive lesions on PSMA-PET) metastatic hormone-sensitive prostate cancer (mHSPC)."	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	50.00%	%	NCT03828838	"Radioligand therapy (RLT) using Lu-177 labelled PSMA is a promising new therapeutic approach to treat metastatic prostate cancer. This tumor-specific treatment is directed against prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer cells. In the last few years, several lutetium-177 (177Lu, emitter) labeled PSMA ligands have been developed and are currently applied to treat metastatic castrate resistant prostate cancer (mCRPC) patients. However, there are no prospective studies published so far using this treatment approach in hormone sensitive setting. In this pilot study patients with hormone sensitive prostate cancer who did not undergo hormonal treatment will be treated with Lu-177 PSMA-617."	Phase 1/2	.	.	.	41.6 h	.	2 cycles	"A first cycle of 3 GBq, followed by a second cycle with 3-6 GBq after 7-9 weeks"	.	"A pilot study (NCT03828838) showed that treatment with lutetium Lu 177 vipivotide tetraxetan was effective in patients with PSMA-expressing, low volume (&ge; 1 but &le; 10 positive lesions on PSMA-PET) metastatic hormone-sensitive prostate cancer (mHSPC). After 2 cycles of lutetium Lu 177 vipivotide tetraxetan (a first cycle of 3 GBq, followed by a second cycle with 3-6 GBq after 7-9 weeks), 5 of 10 patients showed a > 50% PSA reduction and in one patient, PSA was undetectable."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	66.00%	%	NCT03392428	"This open label, randomised, stratified, 2-arm, multicentre, phase 2 trial aims to determine the activity and safety of Lu-PSMA vs cabazitaxel in men with progressive metastatic castration resistant prostate cancer"	Phase 2	65 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	&le;6 cycles every 6 weeks	6.0-8.5 GBq	.	"65 of 99 patients treated with lutetium Lu 177 vipivotide tetraxetan 6.0-8.5 GBq every 6 weeks for up to 6 cycles (n = 99) compared with 37 of 101 patients receiving cabazitaxel 20 mg/m<sup>2</sup> every 3 weeks for up to 10 cycles achieved a PSA reduction of &ge; 50% from baseline [66% vs 37%; treatment difference 29% (95% CI 16-42); p < 0.0001 (ITT analysis)]. Lutetium Lu 177 vipivotide tetraxetan also delayed disease progression [HR 0.63 (95% CI 0.46-0.86;) p = 0.0028], radiographic progression [0.64 (95% CI 0.46-0.88); p = 0.0070] and PSA PFS [0.60 (95% CI 0.44-0.83); p = 0.0017] compared with cabazitaxel."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Delayed radiographic progression	64%	%	NCT03392428	"This open label, randomised, stratified, 2-arm, multicentre, phase 2 trial aims to determine the activity and safety of Lu-PSMA vs cabazitaxel in men with progressive metastatic castration resistant prostate cancer"	Phase 2	65 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	&le;6 cycles every 6 weeks	6.0-8.5 GBq	.	"65 of 99 patients treated with lutetium Lu 177 vipivotide tetraxetan 6.0-8.5 GBq every 6 weeks for up to 6 cycles (n = 99) compared with 37 of 101 patients receiving cabazitaxel 20 mg/m<sup>2</sup> every 3 weeks for up to 10 cycles achieved a PSA reduction of &ge; 50% from baseline [66% vs 37%; treatment difference 29% (95% CI 16-42); p < 0.0001 (ITT analysis)]. Lutetium Lu 177 vipivotide tetraxetan also delayed disease progression [HR 0.63 (95% CI 0.46-0.86;) p = 0.0028], radiographic progression [0.64 (95% CI 0.46-0.88); p = 0.0070] and PSA PFS [0.60 (95% CI 0.44-0.83); p = 0.0017] compared with cabazitaxel."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Delayed progression-free survival	60%	%	NCT03392428	"This open label, randomised, stratified, 2-arm, multicentre, phase 2 trial aims to determine the activity and safety of Lu-PSMA vs cabazitaxel in men with progressive metastatic castration resistant prostate cancer"	Phase 2	65 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	&le;6 cycles every 6 weeks	6.0-8.5 GBq	.	"65 of 99 patients treated with lutetium Lu 177 vipivotide tetraxetan 6.0-8.5 GBq every 6 weeks for up to 6 cycles (n = 99) compared with 37 of 101 patients receiving cabazitaxel 20 mg/m<sup>2</sup> every 3 weeks for up to 10 cycles achieved a PSA reduction of &ge; 50% from baseline [66% vs 37%; treatment difference 29% (95% CI 16-42); p < 0.0001 (ITT analysis)]. Lutetium Lu 177 vipivotide tetraxetan also delayed disease progression [HR 0.63 (95% CI 0.46-0.86;) p = 0.0028], radiographic progression [0.64 (95% CI 0.46-0.88); p = 0.0070] and PSA PFS [0.60 (95% CI 0.44-0.83); p = 0.0017] compared with cabazitaxel."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	60.00%	%	CTRI/2019/12/022282	"This was an investigator-initiated, randomized, parallel group, open-label, and phase 2 non-inferiority trial conducted at a tertiary care institution. Between December 2019 and March 2021, patients with biopsy-proven adenocarcinoma prostate and castration-resistant disease were recruited. Patients were considered eligible if they had metastatic disease on 68 Ga-PSMA-11 PET/CT with significant PSMA expression. Significant PSMA expression was defined as tracer avidity of at least 80% of the lesions being significantly (1.5 times) greater than that of normal liver with none of the lesions having uptake less than that of liver. Only chemotherapy-nave patients were considered for inclusion in this trial; however, patients with prior treatment of NAADs were also included. The patients were required to have Eastern Cooperative Oncology Group (ECOG) performance score2, and adequate haematological, renal, and liver function reserve (Supplementary Table 1). Patients with histological evidence of sarcomatous, spindle-cell or small-cell differentiation, and Sjogren syndrome were excluded. Informed written consent was obtained from the patients prior to inclusion in the study. The study was approved by the Institute Ethics Committee (INT/IEC/2019/001972) and was conducted in accordance with the guidelines enshrined in the Declaration of Helsinki. The trial was also prospectively registered at the Clinical Trials Registry-India (CTRI/2019/12/022282)."	Phase 2	15 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	"Every 8weeks, up to 4 cycles"	6.0-7.4 GBq/cycle	.	"60% of patients (9/15) in the lutetium Lu 177 vipivotide tetraxetan arm and 40% (8/20) in the docetaxel arm achieved a &ge; 50% decline in PSA from baseline [between-group difference 20%; 95% CI -12 to 47 (noninferiority margin of -15 in per protocol analysis achieved)]. Patients were administered lutetium Lu 177 vipivotide tetraxetan (6.0-7.4 GBq/cycle, every 8 weeks, up to 4 cycles) or docetaxel (75 mg/m<sup>2</sup>/cycle, every 3 weeks, up to 10 cycles)."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	61.00%	%	ACTRN12618001073291	"Background: Trials of lutetium prostate specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC) have demonstrated good safety and efficacy, but combination strategies may improve outcomes. Idronoxil is a synthetic flavonoid derivative with radiosensitising properties. 2. Objective: To evaluate the safety and activity of 177Lu PSMA 617 (LuPSMA-617) in combination with idronoxil suppositories (NOX66) in patients with end-stage mCRPC. 3. Design, setting, and participants: Thirty-two men with progressive mCRPC previously treated with taxane-based chemotherapy (91% treated with both docetaxel and cabazitaxel) and abiraterone and/or enzalutamide were enrolled in this phase I dose escalation study with phase II dose expansion. 4. Intervention: Screening with 68Ga PSMA and 18F-fludeoxyglucose positron emission tomography (PET)/computed tomography (CT) was performed. Men received up to six cycles of LuPSMA-617 (7.5 GBq) on day 1, with escalating doses of NOX66 on days 110 of a 6-wk cycle. Cohort 1 (n = 8) received 400 mg and cohort 2 (n = 24) 800 mg of NOX66. 5. Outcome measurements and statistical analysis: Adverse events (AEs), pain inventory scores, prostate-specific antigen (PSA) response, progression-free survival, and overall survival were evaluated."	Phase 1/2	56 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	On day 1 of each 6-week cycle	7.5 GBq	.	"A > 50% reduction in PSA after administration of up to 6 cycles of lutetium Lu 177 vipivotide tetraxetan plus idronoxil (a synthetic flavonoid derivative with radiosensitising properties) was seen in 34 of 56 (61%) patients with progressive mCRPC previously treated with AR pathway inhibition and taxanes in the phase 1/2 LuPin trial (ACTRN12618001073291). The median PSA PFS was 7.5 months and median OS was 19.7 months. Patients received lutetium Lu 177 vipivotide tetraxetan 7.5 GBq on day 1 of each 6-week cycle, with escalating doses of NOX66 on days 1-10 of a 6-week cycle."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	7.5 months	months	ACTRN12618001073291	"Background: Trials of lutetium prostate specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC) have demonstrated good safety and efficacy, but combination strategies may improve outcomes. Idronoxil is a synthetic flavonoid derivative with radiosensitising properties. 2. Objective: To evaluate the safety and activity of 177Lu PSMA 617 (LuPSMA-617) in combination with idronoxil suppositories (NOX66) in patients with end-stage mCRPC. 3. Design, setting, and participants: Thirty-two men with progressive mCRPC previously treated with taxane-based chemotherapy (91% treated with both docetaxel and cabazitaxel) and abiraterone and/or enzalutamide were enrolled in this phase I dose escalation study with phase II dose expansion. 4. Intervention: Screening with 68Ga PSMA and 18F-fludeoxyglucose positron emission tomography (PET)/computed tomography (CT) was performed. Men received up to six cycles of LuPSMA-617 (7.5 GBq) on day 1, with escalating doses of NOX66 on days 110 of a 6-wk cycle. Cohort 1 (n = 8) received 400 mg and cohort 2 (n = 24) 800 mg of NOX66. 5. Outcome measurements and statistical analysis: Adverse events (AEs), pain inventory scores, prostate-specific antigen (PSA) response, progression-free survival, and overall survival were evaluated."	Phase 1/2	56 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	On day 1 of each 6-week cycle	7.5 GBq	.	"A > 50% reduction in PSA after administration of up to 6 cycles of lutetium Lu 177 vipivotide tetraxetan plus idronoxil (a synthetic flavonoid derivative with radiosensitising properties) was seen in 34 of 56 (61%) patients with progressive mCRPC previously treated with AR pathway inhibition and taxanes in the phase 1/2 LuPin trial (ACTRN12618001073291). The median PSA PFS was 7.5 months and median OS was 19.7 months. Patients received lutetium Lu 177 vipivotide tetraxetan 7.5 GBq on day 1 of each 6-week cycle, with escalating doses of NOX66 on days 1-10 of a 6-week cycle."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	19.7 months	months	ACTRN12618001073291	"Background: Trials of lutetium prostate specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC) have demonstrated good safety and efficacy, but combination strategies may improve outcomes. Idronoxil is a synthetic flavonoid derivative with radiosensitising properties. 2. Objective: To evaluate the safety and activity of 177Lu PSMA 617 (LuPSMA-617) in combination with idronoxil suppositories (NOX66) in patients with end-stage mCRPC. 3. Design, setting, and participants: Thirty-two men with progressive mCRPC previously treated with taxane-based chemotherapy (91% treated with both docetaxel and cabazitaxel) and abiraterone and/or enzalutamide were enrolled in this phase I dose escalation study with phase II dose expansion. 4. Intervention: Screening with 68Ga PSMA and 18F-fludeoxyglucose positron emission tomography (PET)/computed tomography (CT) was performed. Men received up to six cycles of LuPSMA-617 (7.5 GBq) on day 1, with escalating doses of NOX66 on days 110 of a 6-wk cycle. Cohort 1 (n = 8) received 400 mg and cohort 2 (n = 24) 800 mg of NOX66. 5. Outcome measurements and statistical analysis: Adverse events (AEs), pain inventory scores, prostate-specific antigen (PSA) response, progression-free survival, and overall survival were evaluated."	Phase 1/2	56 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	On day 1 of each 6-week cycle	7.5 GBq	.	"A > 50% reduction in PSA after administration of up to 6 cycles of lutetium Lu 177 vipivotide tetraxetan plus idronoxil (a synthetic flavonoid derivative with radiosensitising properties) was seen in 34 of 56 (61%) patients with progressive mCRPC previously treated with AR pathway inhibition and taxanes in the phase 1/2 LuPin trial (ACTRN12618001073291). The median PSA PFS was 7.5 months and median OS was 19.7 months. Patients received lutetium Lu 177 vipivotide tetraxetan 7.5 GBq on day 1 of each 6-week cycle, with escalating doses of NOX66 on days 1-10 of a 6-week cycle."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	54.00%	%	NCT03042468	"The purpose of this study is to find the highest dose level of the study drug, 177Lu-PSMA-617 that can be given without severe side effects for advanced prostate cancer."	Phase 1/2	27 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	7.4-22 gbq on days 1 and 15 in the p hase 1 dose-escalation co hort (n = 29); 22gbq on days 1 and 15 in the p hase 2 co hort (n = 21)	22 GBq	.	A phase 1/2 study (NCT03042468) found that a single cycle of fractionated-dose of lutetium Lu 177 vipivotide tetraxetan [7.4-22 GBq on days 1 and 15 in the phase 1 dose-escalation cohort (n = 29); 22GBq on days 1 and 15 in the phase 2 cohort (n = 21); 27 patients treated at 22 GBq] was effective in patients with progressive mCRPC. A >50% PSA reduction was seen in 27 of 50 patients (54%); median PSA PFS was 5.6 months and median OS was 15.2 months.	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	5.6 months	months	NCT03042468	"The purpose of this study is to find the highest dose level of the study drug, 177Lu-PSMA-617 that can be given without severe side effects for advanced prostate cancer."	Phase 1/2	27 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	7.4-22 gbq on days 1 and 15 in the p hase 1 dose-escalation co hort (n = 29); 22gbq on days 1 and 15 in the p hase 2 co hort (n = 21)	22 GBq	.	A phase 1/2 study (NCT03042468) found that a single cycle of fractionated-dose of lutetium Lu 177 vipivotide tetraxetan [7.4-22 GBq on days 1 and 15 in the phase 1 dose-escalation cohort (n = 29); 22GBq on days 1 and 15 in the phase 2 cohort (n = 21); 27 patients treated at 22 GBq] was effective in patients with progressive mCRPC. A >50% PSA reduction was seen in 27 of 50 patients (54%); median PSA PFS was 5.6 months and median OS was 15.2 months.	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	15.2 months	months	NCT03042468	"The purpose of this study is to find the highest dose level of the study drug, 177Lu-PSMA-617 that can be given without severe side effects for advanced prostate cancer."	Phase 1/2	27 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	7.4-22 gbq on days 1 and 15 in the p hase 1 dose-escalation co hort (n = 29); 22gbq on days 1 and 15 in the p hase 2 co hort (n = 21)	22 GBq	.	A phase 1/2 study (NCT03042468) found that a single cycle of fractionated-dose of lutetium Lu 177 vipivotide tetraxetan [7.4-22 GBq on days 1 and 15 in the phase 1 dose-escalation cohort (n = 29); 22GBq on days 1 and 15 in the phase 2 cohort (n = 21); 27 patients treated at 22 GBq] was effective in patients with progressive mCRPC. A >50% PSA reduction was seen in 27 of 50 patients (54%); median PSA PFS was 5.6 months and median OS was 15.2 months.	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	52.00%	%	NCT04833517	"This prospective registry aims to assess outcome and toxicity of targeted radionuclide therapies in patients with advanced prostate cancer in clinical routine. While the major investigated treatment modality is prostate-specific membrane antigen (PSMA)-targeted radioligand therapy, also other radionuclide therapies such as Ra223 and liver-directed radioembolization are included. The investigators believe that prospectively assessed long-term outcome data on implementation of radionuclide therapy, especially in the palliative setting of advanced mCRPC, help to better define the real benefits and risks of the respective treatment modalities for patients regarding survival and quality-of-life."	Phase 2	254 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	"3 median number cycles, delivered at a median interval of 5.7 weeks"	6.5 GBq/cycle (median cumulative dose 21.2 GBq)	.	"A &ge; 50% reduction in PSA was seen in 52.0% of patients (132/254); at a median follow-up of 14.5 months, median PSA PFS was 5.5 months and median OS was 14.5 months. The median dose of lutetium Lu 177 vipivotide tetraxetan was 6.5 GBq/cycle (median cumulative dose 21.2 GBq), the median number cycles was 3, delivered at a median interval of 5.7 weeks."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	5.5 months	months	NCT04833517	"This prospective registry aims to assess outcome and toxicity of targeted radionuclide therapies in patients with advanced prostate cancer in clinical routine. While the major investigated treatment modality is prostate-specific membrane antigen (PSMA)-targeted radioligand therapy, also other radionuclide therapies such as Ra223 and liver-directed radioembolization are included. The investigators believe that prospectively assessed long-term outcome data on implementation of radionuclide therapy, especially in the palliative setting of advanced mCRPC, help to better define the real benefits and risks of the respective treatment modalities for patients regarding survival and quality-of-life."	Phase 2	254 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	"3 median number cycles, delivered at a median interval of 5.7 weeks"	6.5 GBq/cycle (median cumulative dose 21.2 GBq)	.	"A &ge; 50% reduction in PSA was seen in 52.0% of patients (132/254); at a median follow-up of 14.5 months, median PSA PFS was 5.5 months and median OS was 14.5 months. The median dose of lutetium Lu 177 vipivotide tetraxetan was 6.5 GBq/cycle (median cumulative dose 21.2 GBq), the median number cycles was 3, delivered at a median interval of 5.7 weeks."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	14.5 months	months	NCT04833517	"This prospective registry aims to assess outcome and toxicity of targeted radionuclide therapies in patients with advanced prostate cancer in clinical routine. While the major investigated treatment modality is prostate-specific membrane antigen (PSMA)-targeted radioligand therapy, also other radionuclide therapies such as Ra223 and liver-directed radioembolization are included. The investigators believe that prospectively assessed long-term outcome data on implementation of radionuclide therapy, especially in the palliative setting of advanced mCRPC, help to better define the real benefits and risks of the respective treatment modalities for patients regarding survival and quality-of-life."	Phase 2	254 patients with metastatic castration-resistant prostate cancer.	.	.	41.6 h	.	"3 median number cycles, delivered at a median interval of 5.7 weeks"	6.5 GBq/cycle (median cumulative dose 21.2 GBq)	.	"A &ge; 50% reduction in PSA was seen in 52.0% of patients (132/254); at a median follow-up of 14.5 months, median PSA PFS was 5.5 months and median OS was 14.5 months. The median dose of lutetium Lu 177 vipivotide tetraxetan was 6.5 GBq/cycle (median cumulative dose 21.2 GBq), the median number cycles was 3, delivered at a median interval of 5.7 weeks."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00218	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	50.00%	%	NCT03828838	"Radioligand therapy (RLT) using Lu-177 labelled PSMA is a promising new therapeutic approach to treat metastatic prostate cancer. This tumor-specific treatment is directed against prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer cells. In the last few years, several lutetium-177 (177Lu, emitter) labeled PSMA ligands have been developed and are currently applied to treat metastatic castrate resistant prostate cancer (mCRPC) patients. However, there are no prospective studies published so far using this treatment approach in hormone sensitive setting. In this pilot study patients with hormone sensitive prostate cancer who did not undergo hormonal treatment will be treated with Lu-177 PSMA-617."	Phase 1/2	10 patients with low volume (&ge; 1 but &le; 10 positive lesions on PSMA-PET) metastatic hormone-sensitive prostate cancer.	.	.	41.6 h	.	2 cycles	"A first cycle of 3 GBq, followed by a second cycle with 3-6 GBq after 7-9 weeks"	.	"After 2 cycles of lutetium Lu 177 vipivotide tetraxetan (a first cycle of 3 GBq, followed by a second cycle with 3-6 GBq after 7-9 weeks), 5 of 10 patients showed a > 50% PSA reduction and in one patient, PSA was undetectable."	"Lutetium Lu 177 vipivotide tetraxetan is a PSMA-binding ligand bound to a DOTA chelator (i.e., tetraxetan) radiolabeled with lutetium-177. Once lutetium Lu 177 vipivotide tetraxetan is bound to PSMA-expressing cells, the beta-minus emission from lutetium-177 delivers radiation to PSMA-expressing and surrounding cells, inducing DNA damage that leads to cell death. The exposure-efficacy relationships of lutetium Lu 177 vipivotide tetraxetan and the time course of the pharmacodynamic response are not fully characterized [9]. Lutetium-177 decays to a stable hafnium-177 with a physical half-life of 6.647 days by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (&gamma;) of 0.208 MeV (11%) and 0.113 MeV (6.4%)."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	27.78%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Nineteen patients, all with progressive, heavily treated disease, were identified. Sites of tumor origin were: pancreas (74%), small bowel (11%), rectum (11%), and lung (5%); median Ki-67 was 32% (range 22-56). Thirteen patients (68%) completed all four <sup>177</sup>Lu-DOTATATE cycles. Best response (N = 18 evaluable) was: 5/18 (28%) partial response, 8/18 (44%) stable disease, and 5/18 (28%) disease progression. Median PFS was 13.1 months (95% CI: 8.7-20.9)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	44.44%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Nineteen patients, all with progressive, heavily treated disease, were identified. Sites of tumor origin were: pancreas (74%), small bowel (11%), rectum (11%), and lung (5%); median Ki-67 was 32% (range 22-56). Thirteen patients (68%) completed all four <sup>177</sup>Lu-DOTATATE cycles. Best response (N = 18 evaluable) was: 5/18 (28%) partial response, 8/18 (44%) stable disease, and 5/18 (28%) disease progression. Median PFS was 13.1 months (95% CI: 8.7-20.9)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	27.70%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Nineteen patients, all with progressive, heavily treated disease, were identified. Sites of tumor origin were: pancreas (74%), small bowel (11%), rectum (11%), and lung (5%); median Ki-67 was 32% (range 22-56). Thirteen patients (68%) completed all four <sup>177</sup>Lu-DOTATATE cycles. Best response (N = 18 evaluable) was: 5/18 (28%) partial response, 8/18 (44%) stable disease, and 5/18 (28%) disease progression. Median PFS was 13.1 months (95% CI: 8.7-20.9)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	72%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Nineteen patients, all with progressive, heavily treated disease, were identified. Sites of tumor origin were: pancreas (74%), small bowel (11%), rectum (11%), and lung (5%); median Ki-67 was 32% (range 22-56). Thirteen patients (68%) completed all four <sup>177</sup>Lu-DOTATATE cycles. Best response (N = 18 evaluable) was: 5/18 (28%) partial response, 8/18 (44%) stable disease, and 5/18 (28%) disease progression. Median PFS was 13.1 months (95% CI: 8.7-20.9)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	13.1 months	months	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Nineteen patients, all with progressive, heavily treated disease, were identified. Sites of tumor origin were: pancreas (74%), small bowel (11%), rectum (11%), and lung (5%); median Ki-67 was 32% (range 22-56). Thirteen patients (68%) completed all four <sup>177</sup>Lu-DOTATATE cycles. Best response (N = 18 evaluable) was: 5/18 (28%) partial response, 8/18 (44%) stable disease, and 5/18 (28%) disease progression. Median PFS was 13.1 months (95% CI: 8.7-20.9)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 alopecia	26%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 anemia	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 ascites	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 dizziness	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 edema	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 hemorrhage	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 hyperglycemia	16%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 hypertension	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 irregular menstruation	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 leukopenia	16%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 leukopenia	11%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 liver injury	21%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 myopathy	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 nausea	11%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 thrombocytosis	21%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 thrombocytosis	11%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 nausea	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 weight loss	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 anemia	21%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 leukopenia	16%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 neutropenia	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 pancytopenia	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 thrombocytopenia	11%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 abdominal distension	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 anemia	11%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 diarrhea	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 hypertension	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 nausea	5%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00220	PDC_00027	Well-differentiated high-grade neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 thrombocytopenia	16%	%	.	.	.	18 patients with well-differentiated high-grade neuroendocrine tumor.	.	.	.	.	4 cycles	Cumulative activity: 25-28 GBq	.	"Treatment-related toxicities are listed in Table 3. Five patients (26%) experienced dose modifying toxicity during treatment with <sup>177</sup>Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; grade 3/4 in 1 patient, 5%), anemia (7 patients, 37%; grade 3/4 in 2 patients, 11%), leukopenia (6 patients, 32%; grade 3/4 in 0 patients), and elevation of the liver function tests (4 patients, 21%; grade 3/4 in 0 patients)."	"We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with <sup>177</sup>Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations."
REF00224	PDC_00029	Metastatic castration-resistant prostate cancer	"Men with progressive , PSMA-positive metastatic castration-resistant prostate cancer."	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	15.3 months	months	.	.	.	.	.	.	.	.	.	.	.	"Pluvicto's efficacy was evaluated in a randomized (2:1), multicenter, open-label trial that compared Pluvicto plus best standard of care with best standard of care alone in men with progressive, PSMA-positive mCRPC. There was statistically significant improvement in overall survival and radiographic progression-free survival for those who received Pluvicto with best standard of care compared with those who received best standard of care alone. Median overall survival was 15.3 months in the intervention arm and 11.3 months in the control arm, although data interpretation may be limited owing to the number of dropouts from the control arm."	.
REF00227	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Rate of Progression-free survival at 6 months	89.70%	%	.	.	.	29 patients with WHO grade I meningiomas.	.	.	.	.	4 cycles in 8-9 week intervals	3200-7400 MBq per cycle	68Ga-DOTATATE PET/CT assay	"PFS-6 according to WHO grade was analyzed for 72 patients. The 6-month PFS was 89.7% for WHO grade I meningiomas (n = 29); 57.1% for WHO grade II (n = 21) and 0 % for WHO grade III (n = 12). For all grades (n = 86), PFS-6 was 58.1%. PFS-6 for unknown grades was 100%. Based on the available data and following RANO criteria, the best radiological response obtained was stable disease."	"PRRT may be a promising treatment for patients with refractory meningiomas, particularly those with grade I and II meningiomas. The treatment is well tolerated and stabilizes or slows tumor progression for at least a few months."
REF00227	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Rate of Progression-free survival at 6 months	57.10%	%	.	.	.	30 patients with WHO grade II meningiomas.	.	.	.	.	4 cycles in 8-9 week intervals	3200-7400 MBq per cycle	68Ga-DOTATATE PET/CT assay	"PFS-6 according to WHO grade was analyzed for 72 patients. The 6-month PFS was 89.7% for WHO grade I meningiomas (n = 29); 57.1% for WHO grade II (n = 21) and 0 % for WHO grade III (n = 12). For all grades (n = 86), PFS-6 was 58.1%. PFS-6 for unknown grades was 100%. Based on the available data and following RANO criteria, the best radiological response obtained was stable disease."	"PRRT may be a promising treatment for patients with refractory meningiomas, particularly those with grade I and II meningiomas. The treatment is well tolerated and stabilizes or slows tumor progression for at least a few months."
REF00227	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Rate of Progression-free survival at 6 months	0%	%	.	.	.	17 patients with WHO grade III meningiomas.	.	.	.	.	4 cycles in 8-9 week intervals	3200-7400 MBq per cycle	68Ga-DOTATATE PET/CT assay	"PFS-6 according to WHO grade was analyzed for 72 patients. The 6-month PFS was 89.7% for WHO grade I meningiomas (n = 29); 57.1% for WHO grade II (n = 21) and 0 % for WHO grade III (n = 12). For all grades (n = 86), PFS-6 was 58.1%. PFS-6 for unknown grades was 100%. Based on the available data and following RANO criteria, the best radiological response obtained was stable disease."	"PRRT may be a promising treatment for patients with refractory meningiomas, particularly those with grade I and II meningiomas. The treatment is well tolerated and stabilizes or slows tumor progression for at least a few months."
REF00227	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Rate of Progression-free survival at 6 months	100.00%	%	.	.	.	17 patients with unknown WHO grade meningiomas.	.	.	.	.	4 cycles in 8-9 week intervals	3200-7400 MBq per cycle	68Ga-DOTATATE PET/CT assay	"PFS-6 according to WHO grade was analyzed for 72 patients. The 6-month PFS was 89.7% for WHO grade I meningiomas (n = 29); 57.1% for WHO grade II (n = 21) and 0 % for WHO grade III (n = 12). For all grades (n = 86), PFS-6 was 58.1%. PFS-6 for unknown grades was 100%. Based on the available data and following RANO criteria, the best radiological response obtained was stable disease."	"PRRT may be a promising treatment for patients with refractory meningiomas, particularly those with grade I and II meningiomas. The treatment is well tolerated and stabilizes or slows tumor progression for at least a few months."
REF00228	PDC_00028	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 xerostomia	14.30%	%	.	.	.	91 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	"Median 14.3 GBq, range 9.5-20.2"	.	"Grade 1 xerostomia was reported in 13 (14.3%) patients at the baseline and in 22 (24.2%) patients after two cycles of Lu-177 PSMA-I&T/-617 (p < 0.01), with a correlated significant increase of the median sXI-score from 7 (IQR 5.3-9) before to 8 (IQR 6.3-11) after PRLT (p < 0.05). In addition, a moderate correlation of xerostomia symptoms and the sXI-score was found during follow-up (r = 0.43, p < 0.01)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 xerostomia	14.30%	%	.	.	.	91 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	"Median 14.3 GBq, range 9.5-20.2"	.	"Grade 1 xerostomia was reported in 13 (14.3%) patients at the baseline and in 22 (24.2%) patients after two cycles of Lu-177 PSMA-I&T/-617 (p < 0.01), with a correlated significant increase of the median sXI-score from 7 (IQR 5.3-9) before to 8 (IQR 6.3-11) after PRLT (p < 0.05). In addition, a moderate correlation of xerostomia symptoms and the sXI-score was found during follow-up (r = 0.43, p < 0.01)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00028	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 xerostomia	37.50%	%	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"A median of 5.5 (range: 2-9) cycles, median follow up 22.7 months (iqr: 16.4-30.2)"	Median cumulative activity of 35.3 GBq	.	"From the baseline to follow-up, xerostomia became more frequent (grade 1 in 2 (5%) patients at baseline, grade 1 in 15 (37.5%) patients, and grade 2 in 1 (2.5%) patient at follow-up; p < 0.001). No grade 3 xerostomia occurred. The data of the sXI questionnaires were available only at the follow-up, showing a moderate but significant correlation to the subjective dryness of mouth (r = 0.41, p < 0.05)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 xerostomia	37.50%	%	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"A median of 5.5 (range: 2-9) cycles, median follow up 22.7 months (iqr: 16.4-30.2)"	Median cumulative activity of 35.3 GBq	.	"From the baseline to follow-up, xerostomia became more frequent (grade 1 in 2 (5%) patients at baseline, grade 1 in 15 (37.5%) patients, and grade 2 in 1 (2.5%) patient at follow-up; p < 0.001). No grade 3 xerostomia occurred. The data of the sXI questionnaires were available only at the follow-up, showing a moderate but significant correlation to the subjective dryness of mouth (r = 0.41, p < 0.05)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00028	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 xerostomia	2.50%	%	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"A median of 5.5 (range: 2-9) cycles, median follow up 22.7 months (iqr: 16.4-30.2)"	Median cumulative activity of 35.3 GBq	.	"From the baseline to follow-up, xerostomia became more frequent (grade 1 in 2 (5%) patients at baseline, grade 1 in 15 (37.5%) patients, and grade 2 in 1 (2.5%) patient at follow-up; p < 0.001). No grade 3 xerostomia occurred. The data of the sXI questionnaires were available only at the follow-up, showing a moderate but significant correlation to the subjective dryness of mouth (r = 0.41, p < 0.05)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 xerostomia	2.50%	%	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"A median of 5.5 (range: 2-9) cycles, median follow up 22.7 months (iqr: 16.4-30.2)"	Median cumulative activity of 35.3 GBq	.	"From the baseline to follow-up, xerostomia became more frequent (grade 1 in 2 (5%) patients at baseline, grade 1 in 15 (37.5%) patients, and grade 2 in 1 (2.5%) patient at follow-up; p < 0.001). No grade 3 xerostomia occurred. The data of the sXI questionnaires were available only at the follow-up, showing a moderate but significant correlation to the subjective dryness of mouth (r = 0.41, p < 0.05)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00028	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grading stage 0 visual salivary gland scintigraphy	40%	%	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"A median of 5.5 (range: 2-9) cycles, median follow up 22.7 months (iqr: 16.4-30.2)"	Median cumulative activity of 35.3 GBq	Salivary gland scintigraphy assay	"In the visual grading, no significant changes were found on SGS after PRLT (stage 0 in 16 (40%) patients, stage 1 in 16 (40%) patients, and stage 2 in 8 (20%) patients at the baseline; stage 0 in 16 (40%) patients, stage 1 in 20 (50%) patients, and stage 2 in 4 (10%) patients at the follow-up; p = 0.63). A comparison of the Umax and EF of all SG confirmed no significant changes before and after PRLT."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grading stage 0 visual salivary gland scintigraphy	40%	%	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"A median of 5.5 (range: 2-9) cycles, median follow up 22.7 months (iqr: 16.4-30.2)"	Median cumulative activity of 35.3 GBq	Salivary gland scintigraphy assay	"In the visual grading, no significant changes were found on SGS after PRLT (stage 0 in 16 (40%) patients, stage 1 in 16 (40%) patients, and stage 2 in 8 (20%) patients at the baseline; stage 0 in 16 (40%) patients, stage 1 in 20 (50%) patients, and stage 2 in 4 (10%) patients at the follow-up; p = 0.63). A comparison of the Umax and EF of all SG confirmed no significant changes before and after PRLT."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00028	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grading stage 1 visual salivary gland scintigraphy	50%	%	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"A median of 5.5 (range: 2-9) cycles, median follow up 22.7 months (iqr: 16.4-30.2)"	Median cumulative activity of 35.3 GBq	Salivary gland scintigraphy assay	"In the visual grading, no significant changes were found on SGS after PRLT (stage 0 in 16 (40%) patients, stage 1 in 16 (40%) patients, and stage 2 in 8 (20%) patients at the baseline; stage 0 in 16 (40%) patients, stage 1 in 20 (50%) patients, and stage 2 in 4 (10%) patients at the follow-up; p = 0.63). A comparison of the Umax and EF of all SG confirmed no significant changes before and after PRLT."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grading stage 1 visual salivary gland scintigraphy	50%	%	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"A median of 5.5 (range: 2-9) cycles, median follow up 22.7 months (iqr: 16.4-30.2)"	Median cumulative activity of 35.3 GBq	Salivary gland scintigraphy assay	"In the visual grading, no significant changes were found on SGS after PRLT (stage 0 in 16 (40%) patients, stage 1 in 16 (40%) patients, and stage 2 in 8 (20%) patients at the baseline; stage 0 in 16 (40%) patients, stage 1 in 20 (50%) patients, and stage 2 in 4 (10%) patients at the follow-up; p = 0.63). A comparison of the Umax and EF of all SG confirmed no significant changes before and after PRLT."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00028	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grading stage 2 visual salivary gland scintigraphy	10%	%	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"A median of 5.5 (range: 2-9) cycles, median follow up 22.7 months (iqr: 16.4-30.2)"	Median cumulative activity of 35.3 GBq	Salivary gland scintigraphy assay	"In the visual grading, no significant changes were found on SGS after PRLT (stage 0 in 16 (40%) patients, stage 1 in 16 (40%) patients, and stage 2 in 8 (20%) patients at the baseline; stage 0 in 16 (40%) patients, stage 1 in 20 (50%) patients, and stage 2 in 4 (10%) patients at the follow-up; p = 0.63). A comparison of the Umax and EF of all SG confirmed no significant changes before and after PRLT."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grading stage 2 visual salivary gland scintigraphy	10%	%	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"A median of 5.5 (range: 2-9) cycles, median follow up 22.7 months (iqr: 16.4-30.2)"	Median cumulative activity of 35.3 GBq	Salivary gland scintigraphy assay	"In the visual grading, no significant changes were found on SGS after PRLT (stage 0 in 16 (40%) patients, stage 1 in 16 (40%) patients, and stage 2 in 8 (20%) patients at the baseline; stage 0 in 16 (40%) patients, stage 1 in 20 (50%) patients, and stage 2 in 4 (10%) patients at the follow-up; p = 0.63). A comparison of the Umax and EF of all SG confirmed no significant changes before and after PRLT."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 xerostomia	55.56%	%	.	.	.	18 patients with metastatic castration-resistant prostate cancer treated with tandem-cohort PRLT.	.	.	.	.	1 week	A median activity of 4.25 GBq (range 3.6-7.2 GBq)	.	"One-third (6/18) of the patients reported grade 1 xerostomia at the baseline, while, after one cycle of Tandem-PRLT, xerostomia grade 1 in 10/18 patients and grade 2 in 2/18 patients was observed (p = 0.001), and 6/18 patients did not report any xerostomia at the follow-up. There was no patient-requested treatment discontinuation. The sXI-score increased significantly from 9.5 (95%CI: 7.0-14.2) before to 14.0 (95%CI: 11.5-19.6) after Tandem-PRLT (p = 0.005)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00034	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 xerostomia	55.56%	%	.	.	.	18 patients with metastatic castration-resistant prostate cancer treated with tandem-cohort PRLT.	.	.	.	.	1 week	A median activity of 4.0 MBq (range 2.0-7.0 MBq)	.	"One-third (6/18) of the patients reported grade 1 xerostomia at the baseline, while, after one cycle of Tandem-PRLT, xerostomia grade 1 in 10/18 patients and grade 2 in 2/18 patients was observed (p = 0.001), and 6/18 patients did not report any xerostomia at the follow-up. There was no patient-requested treatment discontinuation. The sXI-score increased significantly from 9.5 (95%CI: 7.0-14.2) before to 14.0 (95%CI: 11.5-19.6) after Tandem-PRLT (p = 0.005)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 xerostomia	11.11%	%	.	.	.	18 patients with metastatic castration-resistant prostate cancer treated with tandem-cohort PRLT.	.	.	.	.	1 week	A median activity of 4.25 GBq (range 3.6-7.2 GBq)	.	"One-third (6/18) of the patients reported grade 1 xerostomia at the baseline, while, after one cycle of Tandem-PRLT, xerostomia grade 1 in 10/18 patients and grade 2 in 2/18 patients was observed (p = 0.001), and 6/18 patients did not report any xerostomia at the follow-up. There was no patient-requested treatment discontinuation. The sXI-score increased significantly from 9.5 (95%CI: 7.0-14.2) before to 14.0 (95%CI: 11.5-19.6) after Tandem-PRLT (p = 0.005)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00034	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 xerostomia	11.11%	%	.	.	.	18 patients with metastatic castration-resistant prostate cancer treated with tandem-cohort PRLT.	.	.	.	.	1 week	A median activity of 4.0 MBq (range 2.0-7.0 MBq)	.	"One-third (6/18) of the patients reported grade 1 xerostomia at the baseline, while, after one cycle of Tandem-PRLT, xerostomia grade 1 in 10/18 patients and grade 2 in 2/18 patients was observed (p = 0.001), and 6/18 patients did not report any xerostomia at the follow-up. There was no patient-requested treatment discontinuation. The sXI-score increased significantly from 9.5 (95%CI: 7.0-14.2) before to 14.0 (95%CI: 11.5-19.6) after Tandem-PRLT (p = 0.005)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grading stage 0 visual salivary gland scintigraphy	5.56%	%	.	.	.	18 patients with metastatic castration-resistant prostate cancer treated with tandem-cohort PRLT.	.	.	.	.	1 week	A median activity of 4.25 GBq (range 3.6-7.2 GBq)	Salivary gland scintigraphy assay	"The stage of xerostomia at the baseline according to SGS was 0 in 10/18 patients, 1 in 6/18 patients, and 2 in 2/18 patients, while, at the follow-up, stage 0 was noted in 1/18 patients, stage 1 in 8/18 patients, and stage 2 in 9/18 patients (p < 0.001)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00034	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grading stage 0 visual salivary gland scintigraphy	5.56%	%	.	.	.	18 patients with metastatic castration-resistant prostate cancer treated with tandem-cohort PRLT.	.	.	.	.	1 week	A median activity of 4.0 MBq (range 2.0-7.0 MBq)	Salivary gland scintigraphy assay	"The stage of xerostomia at the baseline according to SGS was 0 in 10/18 patients, 1 in 6/18 patients, and 2 in 2/18 patients, while, at the follow-up, stage 0 was noted in 1/18 patients, stage 1 in 8/18 patients, and stage 2 in 9/18 patients (p < 0.001)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grading stage 1 visual salivary gland scintigraphy	44.44%	%	.	.	.	18 patients with metastatic castration-resistant prostate cancer treated with tandem-cohort PRLT.	.	.	.	.	1 week	A median activity of 4.25 GBq (range 3.6-7.2 GBq)	Salivary gland scintigraphy assay	"The stage of xerostomia at the baseline according to SGS was 0 in 10/18 patients, 1 in 6/18 patients, and 2 in 2/18 patients, while, at the follow-up, stage 0 was noted in 1/18 patients, stage 1 in 8/18 patients, and stage 2 in 9/18 patients (p < 0.001)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00034	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grading stage 1 visual salivary gland scintigraphy	44.44%	%	.	.	.	18 patients with metastatic castration-resistant prostate cancer treated with tandem-cohort PRLT.	.	.	.	.	1 week	A median activity of 4.0 MBq (range 2.0-7.0 MBq)	Salivary gland scintigraphy assay	"The stage of xerostomia at the baseline according to SGS was 0 in 10/18 patients, 1 in 6/18 patients, and 2 in 2/18 patients, while, at the follow-up, stage 0 was noted in 1/18 patients, stage 1 in 8/18 patients, and stage 2 in 9/18 patients (p < 0.001)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grading stage 2 visual salivary gland scintigraphy	50%	%	.	.	.	18 patients with metastatic castration-resistant prostate cancer treated with tandem-cohort PRLT.	.	.	.	.	1 week	A median activity of 4.25 GBq (range 3.6-7.2 GBq)	Salivary gland scintigraphy assay	"The stage of xerostomia at the baseline according to SGS was 0 in 10/18 patients, 1 in 6/18 patients, and 2 in 2/18 patients, while, at the follow-up, stage 0 was noted in 1/18 patients, stage 1 in 8/18 patients, and stage 2 in 9/18 patients (p < 0.001)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00228	PDC_00034	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grading stage 2 visual salivary gland scintigraphy	50%	%	.	.	.	18 patients with metastatic castration-resistant prostate cancer treated with tandem-cohort PRLT.	.	.	.	.	1 week	A median activity of 4.0 MBq (range 2.0-7.0 MBq)	Salivary gland scintigraphy assay	"The stage of xerostomia at the baseline according to SGS was 0 in 10/18 patients, 1 in 6/18 patients, and 2 in 2/18 patients, while, at the follow-up, stage 0 was noted in 1/18 patients, stage 1 in 8/18 patients, and stage 2 in 9/18 patients (p < 0.001)."	"Salivary gland dysfunction after <sup>177</sup>Lu-PSMA-I&T/-617 PRLT has minor clinical relevance, both subjectively and objectively. Even after high cumulative activities, only mild-to-moderate dryness of mouth occurs in a minority of the patients. The prevalence of xerostomia appears to be significantly lower than the historical controls after external radiotherapy, radioiodine therapy, and especially after PRLT with 225Ac-PSMA-617. A validated questionnaire on xerostomia, salivary gland scintigraphy, and PSMA-PET/CT parameters can help to objectify, standardize, and quantify the SG toxicity of PRLT. A decrease of the excretion fraction on SGS and of the metabolic volume on PSMA PET/CT can be early indicators of SG impairment. The co-administration of lower doses of 225Ac in combination with <sup>177</sup>Lu-PSMA-617 (Tandem concept) can decrease severe xerostomia after PRLT with alpha-emitters."
REF00229	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median radiographic progression-free survival (rPFS)	8.7 months	months	.	.	.	831 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Primary outcomes measured radiographic progression-free survival (rPFS) and OS between <sup>177</sup>Lu PSMA-617 RLT plus SOC versus standard of care (SOC) alone. When compared to SOC alone, <sup>177</sup>Lu PSMA-617 plus SOC significantly prolonged rPFS (median, 8.7 vs. 3.4 months; HR for progression or death 0.40; 99.2% CI, 0.29 to 0.57) and median OS (15.3 vs. 11.3 months; HR for death, 0.62; 95% CI, 0.52 to 0.74; p < 0.001)."	.
REF00229	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	15.3 months	months	.	.	.	831 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Primary outcomes measured radiographic progression-free survival (rPFS) and OS between <sup>177</sup>Lu PSMA-617 RLT plus SOC versus standard of care (SOC) alone. When compared to SOC alone, <sup>177</sup>Lu PSMA-617 plus SOC significantly prolonged rPFS (median, 8.7 vs. 3.4 months; HR for progression or death 0.40; 99.2% CI, 0.29 to 0.57) and median OS (15.3 vs. 11.3 months; HR for death, 0.62; 95% CI, 0.52 to 0.74; p < 0.001)."	.
REF00229	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	66.00%	%	.	.	.	200 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	68Ga-PSMA-11 PET/CT assay	"The phase II TheraP trial, compared <sup>177</sup>Lu PSMA-617 to cabazitaxel in 200 men with mCRPC. The primary endpoint was PSA response defined by a reduction of PSA &ge; 50% from baseline. In contrast to the VISION trial, TheraP set PSMA SUVmax requirements of at least one lesion on 68Ga-PSMA-11 PET with SUVmax > 20, and the remaining metastatic lesions SUVmax > 10, and no discordant hypermetabolic disease. PSA responses were more frequent among men in the <sup>177</sup>Lu PSMA-617 group versus the cabazitaxel group (66% vs. 37%, respectively)."	.
REF00229	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	13.5 months	months	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"In a study of 56 patients, Chen et al. found that 23.2% had at least one PSMA (-)/FDG (+) lesion, and that PSA and Gleason score were both higher in these patients with discordant hypermetabolic disease. A sub-analysis of a single center phase II trial of <sup>177</sup>Lu PSMA-617 RLT similarly found that 16/50 patients had at least one PSMA (-)/FDG (+) lesion and were deemed ineligible for <sup>177</sup>Lu PSMA-617 therapy. The OS of these patients with discordant hypermetabolic disease was 2.6 months (compared to 13.5 months for patients that received <sup>177</sup>Lu PSMA-617)."	.
REF00229	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Rate of adverse events	52.70%	%	.	.	.	1192 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"<sup>177</sup>Lu PSMA-617 has been shown to have a low, but significant, rate of adverse events (AE) in several clinical studies. In the phase III VISION study, 52.7% of patients experienced a grade 3 or higher AE, as compared to 38.0% of patients with similar events in the control group. Anemia was the most common grade &ge;3 AE, observed in 12.9% of subjects"	.
REF00229	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Anemia	12.90%	%	.	.	.	1192 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"<sup>177</sup>Lu PSMA-617 has been shown to have a low, but significant, rate of adverse events (AE) in several clinical studies. In the phase III VISION study, 52.7% of patients experienced a grade 3 or higher AE, as compared to 38.0% of patients with similar events in the control group. Anemia was the most common grade &ge;3 AE, observed in 12.9% of subjects"	.
REF00229	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Anemia	19.00%	%	.	.	.	1192 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Additionally, a recently published meta-analysis of 250 studies with a total of 1192 patients similarly found that while grade 3 and 4 toxicities were uncommon, anemia was the highest reported adverse event for both <sup>177</sup>Lu PSMA-617 (0.19 [0.06-0.15]) and <sup>177</sup>Lu PSMAI&T (0.09 [0.05-0.16]). Greater than 35% of patients in the treatment group of the VISION trial experienced fatigue, dry mouth, or nausea, though almost entirely grade &le; 2 AE."	.
REF00229	PDC_00028	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Anemia	9.00%	%	.	.	.	1192 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Additionally, a recently published meta-analysis of 250 studies with a total of 1192 patients similarly found that while grade 3 and 4 toxicities were uncommon, anemia was the highest reported adverse event for both <sup>177</sup>Lu PSMA-617 (0.19 [0.06-0.15]) and <sup>177</sup>Lu PSMAI&T (0.09 [0.05-0.16]). Greater than 35% of patients in the treatment group of the VISION trial experienced fatigue, dry mouth, or nausea, though almost entirely grade &le; 2 AE."	.
REF00229	PDC_00034	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	65.00%	%	.	.	.	26 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A retrospective analysis of 26 men with progressive mCRPC that had undergone several previous therapies, including <sup>177</sup>Lu PSMA-617, found that 225Ac PSMA-617 resulted in a &ge;50% PSA drop in 65% of patients."	.
REF00231	PDC_00005	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	18.7 &plusmn; 0.3 nM	nM	.	.	.	.	Prostate carcinoma	LNCaP cell	162 &plusmn; 4.86 h	.	1 h	.	Gamma counter assay	"The PSMA binding affinities were determined by a competitive binding assay using PSMA-overexpressing LNCaP human prostate carcinoma cell homogenates and a known high affinity <sup>125</sup>I-labeled PSMA ligand, [<sup>125</sup>I]MIP-1095, as the radioligand. The IC50 values for the metal-free PSMA-inhibiting compounds and metal complexes are summarized in Table 1. PSMA-617 and P16-093 were included in this study as reference compounds. The PSMA affinities of 4 and 7 as well as their natLu-labeled complexes were comparable to those of the reference compounds and displayed excellent binding affinities (IC50 = 28.7, 15.4, 18.7, and 20.2 nM, respectively). The addition of the p-iodophenylbutanoyl group in compound 7 did not change the PSMA binding affinity because of the small molecular size and remote position from the PSMA binding site."	"Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis and radionuclide therapy of prostate cancer. This study reports conversion of a previously reported 68Ga-imaging agent, [68Ga]Ga-P16-093, to a Lu-177 radionuclide therapeutic agent. Substitution of the HBED-CC metal chelating group with DOTA(GA)2 led to P17-087 (4) and P17-088 (7). Both agents showed excellent PSMA binding affinity (IC50 = 10-30 nM) comparable to that of recently FDA-approved [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto). Biodistribution studies in PSMA expressing tumor bearing mice showed that [<sup>177</sup>Lu]Lu-4 exhibited very high tumor uptake and a fast blood clearance similar to those of [<sup>177</sup>Lu]Lu-PSMA-617. Conversely, [<sup>177</sup>Lu]Lu-7, containing an albumin binder, extended its blood half-life and exhibited significantly higher uptake and longer tumor residence time than [<sup>177</sup>Lu]Lu-4 and [<sup>177</sup>Lu]Lu-PSMA-617. The switch from chelator HBED-CC to DOTA(GA)2 and the switch from the imaging isotope gallium-68 to the therapeutic isotope lutetium-177 have successfully transformed a PSMA-targeting agent from diagnosis to promising radionuclide therapeutic agents."
REF00231	PDC_00006	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	20.2 &plusmn; 4.6 nM	nM	.	.	.	.	Prostate carcinoma	LNCaP cell	165 &plusmn; 0.99 h	.	1 h	.	Gamma counter assay	"The PSMA binding affinities were determined by a competitive binding assay using PSMA-overexpressing LNCaP human prostate carcinoma cell homogenates and a known high affinity <sup>125</sup>I-labeled PSMA ligand, [<sup>125</sup>I]MIP-1095, as the radioligand. The IC50 values for the metal-free PSMA-inhibiting compounds and metal complexes are summarized in Table 1. PSMA-617 and P16-093 were included in this study as reference compounds. The PSMA affinities of 4 and 7 as well as their natLu-labeled complexes were comparable to those of the reference compounds and displayed excellent binding affinities (IC50 = 28.7, 15.4, 18.7, and 20.2 nM, respectively). The addition of the p-iodophenylbutanoyl group in compound 7 did not change the PSMA binding affinity because of the small molecular size and remote position from the PSMA binding site."	"Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis and radionuclide therapy of prostate cancer. This study reports conversion of a previously reported 68Ga-imaging agent, [68Ga]Ga-P16-093, to a Lu-177 radionuclide therapeutic agent. Substitution of the HBED-CC metal chelating group with DOTA(GA)2 led to P17-087 (4) and P17-088 (7). Both agents showed excellent PSMA binding affinity (IC50 = 10-30 nM) comparable to that of recently FDA-approved [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto). Biodistribution studies in PSMA expressing tumor bearing mice showed that [<sup>177</sup>Lu]Lu-4 exhibited very high tumor uptake and a fast blood clearance similar to those of [<sup>177</sup>Lu]Lu-PSMA-617. Conversely, [<sup>177</sup>Lu]Lu-7, containing an albumin binder, extended its blood half-life and exhibited significantly higher uptake and longer tumor residence time than [<sup>177</sup>Lu]Lu-4 and [<sup>177</sup>Lu]Lu-PSMA-617. The switch from chelator HBED-CC to DOTA(GA)2 and the switch from the imaging isotope gallium-68 to the therapeutic isotope lutetium-177 have successfully transformed a PSMA-targeting agent from diagnosis to promising radionuclide therapeutic agents."
REF00231	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11.1 &plusmn; 0.8 nM	nM	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	1 h	.	Gamma counter assay	"The PSMA binding affinities were determined by a competitive binding assay using PSMA-overexpressing LNCaP human prostate carcinoma cell homogenates and a known high affinity <sup>125</sup>I-labeled PSMA ligand, [<sup>125</sup>I]MIP-1095, as the radioligand. The IC50 values for the metal-free PSMA-inhibiting compounds and metal complexes are summarized in Table 1. PSMA-617 and P16-093 were included in this study as reference compounds. The PSMA affinities of 4 and 7 as well as their natLu-labeled complexes were comparable to those of the reference compounds and displayed excellent binding affinities (IC50 = 28.7, 15.4, 18.7, and 20.2 nM, respectively). The addition of the p-iodophenylbutanoyl group in compound 7 did not change the PSMA binding affinity because of the small molecular size and remote position from the PSMA binding site."	"Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis and radionuclide therapy of prostate cancer. This study reports conversion of a previously reported 68Ga-imaging agent, [68Ga]Ga-P16-093, to a Lu-177 radionuclide therapeutic agent. Substitution of the HBED-CC metal chelating group with DOTA(GA)2 led to P17-087 (4) and P17-088 (7). Both agents showed excellent PSMA binding affinity (IC50 = 10-30 nM) comparable to that of recently FDA-approved [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto). Biodistribution studies in PSMA expressing tumor bearing mice showed that [<sup>177</sup>Lu]Lu-4 exhibited very high tumor uptake and a fast blood clearance similar to those of [<sup>177</sup>Lu]Lu-PSMA-617. Conversely, [<sup>177</sup>Lu]Lu-7, containing an albumin binder, extended its blood half-life and exhibited significantly higher uptake and longer tumor residence time than [<sup>177</sup>Lu]Lu-4 and [<sup>177</sup>Lu]Lu-PSMA-617. The switch from chelator HBED-CC to DOTA(GA)2 and the switch from the imaging isotope gallium-68 to the therapeutic isotope lutetium-177 have successfully transformed a PSMA-targeting agent from diagnosis to promising radionuclide therapeutic agents."
REF00233	PDC_00027	Metastatic medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	33.33%	%	.	.	.	6 patients with medullary thyroid cancer (3 males and 3 females).	.	.	.	.	3 cycles	"5.7 GBq/cycle (range, 2.6-7.4 GBq)"	PET/CT assay	"Four of the 17 patients with positive SSTR-PET were scheduled for PRRT. In addition, 2 patients had positive 99mTc-octreotide scintigraphy results (Krenning score &ge; 2) and were scheduled for PRRT. Two of the 6 patients who underwent PRRT showed PR, 2 SD and 2 PD. Two patients died during the follow-up period. Median overall survival was 19 months (95% CI: 5.52-29.48). There were no cases of significant toxicity."	"Radiolabeled somatostatin analogs are contributive for the management of recurrent MTC. 68Ga-DOTATAE PET-CT showed a relatively high detection rate in recurrent MTC. In addition, PRRT with <sup>177</sup>Lu-DOTATATE was found to be a safe alternative therapeutic option for MTC."
REF00233	PDC_00027	Metastatic medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	33.33%	%	.	.	.	6 patients with medullary thyroid cancer (3 males and 3 females).	.	.	.	.	3 cycles	"5.7 GBq/cycle (range, 2.6-7.4 GBq)"	PET/CT assay	"Four of the 17 patients with positive SSTR-PET were scheduled for PRRT. In addition, 2 patients had positive 99mTc-octreotide scintigraphy results (Krenning score &ge; 2) and were scheduled for PRRT. Two of the 6 patients who underwent PRRT showed PR, 2 SD and 2 PD. Two patients died during the follow-up period. Median overall survival was 19 months (95% CI: 5.52-29.48). There were no cases of significant toxicity."	"Radiolabeled somatostatin analogs are contributive for the management of recurrent MTC. 68Ga-DOTATAE PET-CT showed a relatively high detection rate in recurrent MTC. In addition, PRRT with <sup>177</sup>Lu-DOTATATE was found to be a safe alternative therapeutic option for MTC."
REF00233	PDC_00027	Metastatic medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	33.33%	%	.	.	.	6 patients with medullary thyroid cancer (3 males and 3 females).	.	.	.	.	3 cycles	"5.7 GBq/cycle (range, 2.6-7.4 GBq)"	PET/CT assay	"Four of the 17 patients with positive SSTR-PET were scheduled for PRRT. In addition, 2 patients had positive 99mTc-octreotide scintigraphy results (Krenning score &ge; 2) and were scheduled for PRRT. Two of the 6 patients who underwent PRRT showed PR, 2 SD and 2 PD. Two patients died during the follow-up period. Median overall survival was 19 months (95% CI: 5.52-29.48). There were no cases of significant toxicity."	"Radiolabeled somatostatin analogs are contributive for the management of recurrent MTC. 68Ga-DOTATAE PET-CT showed a relatively high detection rate in recurrent MTC. In addition, PRRT with <sup>177</sup>Lu-DOTATATE was found to be a safe alternative therapeutic option for MTC."
REF00233	PDC_00027	Metastatic medullary thyroid carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	19 months	months	.	.	.	6 patients with medullary thyroid cancer (3 males and 3 females).	.	.	.	.	3 cycles	"5.7 GBq/cycle (range, 2.6-7.4 GBq)"	PET/CT assay	"Four of the 17 patients with positive SSTR-PET were scheduled for PRRT. In addition, 2 patients had positive 99mTc-octreotide scintigraphy results (Krenning score &ge; 2) and were scheduled for PRRT. Two of the 6 patients who underwent PRRT showed PR, 2 SD and 2 PD. Two patients died during the follow-up period. Median overall survival was 19 months (95% CI: 5.52-29.48). There were no cases of significant toxicity."	"Radiolabeled somatostatin analogs are contributive for the management of recurrent MTC. 68Ga-DOTATAE PET-CT showed a relatively high detection rate in recurrent MTC. In addition, PRRT with <sup>177</sup>Lu-DOTATATE was found to be a safe alternative therapeutic option for MTC."
REF00237	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	40%	%	.	.	.	90-year-old patient with advanced metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	Prasad et al. observed a 40% PSA decline in a 90-y-old patient with advanced mCRPC who initiated <sup>177</sup>Lu-PSMA-617 while receiving pembrolizumab for locally advanced squamous cell carcinoma.	.
REF00237	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	75.00%	%	NCT03658447	"This investigator driven study will examine the safety, tolerability and efficacy of the combination of 177Lutetium-PSMA (177Lu-PSMA) and pembrolizumab in patients with metastatic Castration Resistant Prostate Cancer (mCRPC). 177Lu-PSMA is a compound that binds to the extra-cellular domain of the prostate-specific membrane antigen. Pembrolizumab is an antibody targeted against anti-programmed cell death 1 (PD-1).This is a single arm study where all patients will be treated with 177Lu-PSMA for upto 6 doses and pembrolizumab for upto 35 cycles."	Phase 1/2	37 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"To interrogate potential synergy between <sup>177</sup>Lu-PSMA-617 and pembrolizumab, the phase Ib/II PRINCE trial (NCT03658447) was initiated. Although the study is ongoing, an interim report details a &ge; 50% PSA decline rate of near 75% among 37 patients."	.
REF00237	PDC_00034	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	70.00%	%	.	.	.	"Heavily pretreated, TRT-naive metastatic castration-resistant prostate cancer patients."	.	.	.	.	.	.	68Ga-PSMA PET assay	"Therapy with 225Ac-PSMA-617 has shown remarkable efficacy (70% rate of PSA decline &ge; 50%, 29% complete response rate from 68Ga-PSMA PET) in heavily pretreated, TRT-nave patients."	.
REF00237	PDC_00034	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	29%	%	.	.	.	"Heavily pretreated, TRT-naive metastatic castration-resistant prostate cancer patients."	.	.	.	.	.	.	68Ga-PSMA PET assay	"Therapy with 225Ac-PSMA-617 has shown remarkable efficacy (70% rate of PSA decline &ge; 50%, 29% complete response rate from 68Ga-PSMA PET) in heavily pretreated, TRT-nave patients."	.
REF00016; REF00239	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	65.20%	%	NCT01578239	"This was a multicenter, stratified, open, randomized, comparator-controlled, parallel-group phase III study comparing treatment with Lutathera plus best supportive care (30 mg Octreotide LAR) to treatment with high dose (60 mg) Octreotide LAR in participants with metastasized or locally advanced, inoperable, somatostatin receptor positive, histologically proven midgut carcinoid tumours with progression despite LAR treatment."	Phase 3	"29 patients who had well-differentiated, metastatic midgut neuroendocrine tumor."	.	.	.	.	Every 8 weeks for a total of 4 cycles	.	.	NETTER-1 demonstrated that treatment with <sup>177</sup>Lu-DOTATATE and octreotide resulted in a progression free survival (PFS) rate of 65.2% vs. 10.8% in the high-dose octreotide group.	<sup>177</sup>Lu-DOTATATE is the first FDA-approved PRRT and utilizes a somatostatin analogue (DOTATATE) covalently bound to the beta-minus emitting radioisotope <sup>177</sup>Lu in order to provide targeted radiation directly to NET cells overexpressing SSTRs (primarily SSTR2).
REF00199; REF00239	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	48.0 months	months	NCT01578239	"This was a multicenter, stratified, open, randomized, comparator-controlled, parallel-group phase III study comparing treatment with Lutathera plus best supportive care (30 mg Octreotide LAR) to treatment with high dose (60 mg) Octreotide LAR in participants with metastasized or locally advanced, inoperable, somatostatin receptor positive, histologically proven midgut carcinoid tumours with progression despite LAR treatment."	Phase 3	"Patients were 18 years and older with locally advanced or metastatic, well differentiated, somatostatin receptor-positive midgut neuroendocrine tumours (Karnofsky performance status score 60) and disease progression on fixed-dose long-acting octreotide."	.	.	.	.	Every 8 weeks for a total of 4 cycles	.	.	"In 2021, Strosberg et al. provided updated survival results from the NETTER-1 trial, which showed no statistically significant difference in median overall survival in the <sup>177</sup>Lu-DOTATATE group and octreotide group vs. the control group (48.0 months vs. 36.3 months, respectively, p = 0.30), a result that was likely impacted by the high rate of crossover (36%) in the investigational arm of the study."	<sup>177</sup>Lu-DOTATATE is the first FDA-approved PRRT and utilizes a somatostatin analogue (DOTATATE) covalently bound to the beta-minus emitting radioisotope <sup>177</sup>Lu in order to provide targeted radiation directly to NET cells overexpressing SSTRs (primarily SSTR2).
REF00241	PDC_00004	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median detection ratio	91.10%	%	.	.	.	75 patients with histologically confirmed neuroendocrine tumours and routine clinical.	.	.	.	.	.	.	.	"In total, 4,709 different tumor lesions were detected: 3,454 with 68Ga-DOTATATE/NOC and 4,278 with 18F-AlF-OC. The mean DR with 18F-AlF-OC was significantly higher than with 68Ga-DOTATATE/NOC (91.1% vs. 75.3%; P < 10-5)."	18F-AlF-OC is noninferior and even superior to 68Ga-DOTATATE/NOC PET in NET patients. This validates 18F-AlF-OC as an option for clinical practice somatostatin receptor PET.
REF00241	PDC_00039	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median detection ratio	75.30%	%	.	.	.	75 patients with histologically confirmed neuroendocrine tumours and routine clinical.	.	.	.	.	.	.	.	"In total, 4,709 different tumor lesions were detected: 3,454 with 68Ga-DOTATATE/NOC and 4,278 with 18F-AlF-OC. The mean DR with 18F-AlF-OC was significantly higher than with 68Ga-DOTATATE/NOC (91.1% vs. 75.3%; P < 10-5)."	18F-AlF-OC is noninferior and even superior to 68Ga-DOTATATE/NOC PET in NET patients. This validates 18F-AlF-OC as an option for clinical practice somatostatin receptor PET.
REF00241	PDC_00004	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Difference in detection ratio	15.80%	%	.	.	.	75 patients with histologically confirmed neuroendocrine tumours and routine clinical.	.	.	.	.	.	.	.	"The resulting mean DDR was 15.8%, with a lower margin of the 95% CI (95% CI, 9.6%-22.0%) higher than -15%, which is the prespecified boundary for noninferiority. The mean DDRs for the 68Ga-DOTATATE and 68Ga-DOTANOC subgroups were 11.8% (95% CI, 4.3-19.3) and 27.5% (95% CI, 17.8-37.1), respectively."	18F-AlF-OC is noninferior and even superior to 68Ga-DOTATATE/NOC PET in NET patients. This validates 18F-AlF-OC as an option for clinical practice somatostatin receptor PET.
REF00241	PDC_00039	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Difference in detection ratio	11.80%	%	.	.	.	75 patients with histologically confirmed neuroendocrine tumours and routine clinical.	.	.	.	.	.	.	.	"The resulting mean DDR was 15.8%, with a lower margin of the 95% CI (95% CI, 9.6%-22.0%) higher than -15%, which is the prespecified boundary for noninferiority. The mean DDRs for the 68Ga-DOTATATE and 68Ga-DOTANOC subgroups were 11.8% (95% CI, 4.3-19.3) and 27.5% (95% CI, 17.8-37.1), respectively."	18F-AlF-OC is noninferior and even superior to 68Ga-DOTATATE/NOC PET in NET patients. This validates 18F-AlF-OC as an option for clinical practice somatostatin receptor PET.
REF00241	PDC_00038	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Difference in detection ratio	27.50%	%	.	.	.	75 patients with histologically confirmed neuroendocrine tumours and routine clinical.	.	.	.	.	.	.	.	"The resulting mean DDR was 15.8%, with a lower margin of the 95% CI (95% CI, 9.6%-22.0%) higher than -15%, which is the prespecified boundary for noninferiority. The mean DDRs for the 68Ga-DOTATATE and 68Ga-DOTANOC subgroups were 11.8% (95% CI, 4.3-19.3) and 27.5% (95% CI, 17.8-37.1), respectively."	18F-AlF-OC is noninferior and even superior to 68Ga-DOTATATE/NOC PET in NET patients. This validates 18F-AlF-OC as an option for clinical practice somatostatin receptor PET.
REF00242; REF00081	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	64.00%	%	ACTRN12615000912583	.	Phase 2	Seventy-five patients were screened to identify 50 evaluable patients. Sixteen patients were excluded because of either low PSMA expression (n = 8) or discordant sites of 18F-FDG-positive PSMA-negative disease. Fifty patients with PSMA-avid metastatic castration-resistant prostate cancer who had progressed after standard therapies received up to 4 cycles of <sup>177</sup>Lu-PSMA every 6 wk.	.	.	41.1 &plusmn; 9.3 h	.	Every 6 weeks for up to six doses	7.4 GBq	.	"The overall results of this study are in good agreement with those reported in previous retrospective studies. In an extension of this study, the group around Hofman reported even higher efficacy, with PSA response rates of at least 50% in 64% of all cases, whereas toxicity was similar to the first results."	"After binding to the PSMA receptor, [<sup>177</sup>Lu]Lu-PSMA-617 is internalized into the PSMA positive cells, resulting in a long retention within these cells; the high energy electrons emitted during the decay can selectively induce tissue and DNA damage, leading to cell death."
REF00242	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Xerostomia	30%	%	.	.	.	.	.	.	41.1 &plusmn; 9.3 h	.	Every 6 weeks for up to six doses	7.4 GBq	.	"As described above, most of the observed toxicities have been low grade, with xerostomia or dry mouth being the most common adverse reactions in >30% of patients."	"After binding to the PSMA receptor, [<sup>177</sup>Lu]Lu-PSMA-617 is internalized into the PSMA positive cells, resulting in a long retention within these cells; the high energy electrons emitted during the decay can selectively induce tissue and DNA damage, leading to cell death."
REF00242; REF00177	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 3/4 kidney injury	3%	%	NCT03511664	.	Phase 3	"Of the 1003 patients who underwent scanning, 831 (82.9%) were judged to have met all the trial eligibility criteria, including the PSMA imaging criteria, and were randomly assigned, between June 4, 2018, and October 23, 2019, to receive either <sup>177</sup>Lu-PSMA-617 plus protocol-permitted standard care (551 patients) or standard care alone (280)."	.	.	41.1 &plusmn; 9.3 h	.	Every 6 weeks for up to six doses	7.4 GBq	.	"Observed hematological toxicity is most pronounced in patients with extensive bone metastases, as the uptake in these metastases may lead to radiation-induced damage in the neighboring bone marrow. Renal toxicity resulting in grade 3 or 4 kidney injury occurred in 3% of patients during the VISION trial."	"After binding to the PSMA receptor, [<sup>177</sup>Lu]Lu-PSMA-617 is internalized into the PSMA positive cells, resulting in a long retention within these cells; the high energy electrons emitted during the decay can selectively induce tissue and DNA damage, leading to cell death."
REF00242; REF00145	PDC_00029	Metastatic castration-resistant prostate cancer	"In this retrospective cohort study, we assessed 195 men with progressive mCRPC who had received therapy with <sup>177</sup>Lu-PSMA as second- or third-line after standard therapeutic interventions."	Identified from the Human Clinical Data	High Expreesion	Mild nephrotoxic risk	4.50%	%	.	.	.	.	.	.	41.1 &plusmn; 9.3 h	.	Every 6 weeks for up to six doses	7.4 GBq	.	"In a retrospective Australian study, the renal outcome during a longer follow-up time after treatment (median time 8 months) with either [<sup>177</sup>Lu]Lu-PSMA-617 or [<sup>177</sup>Lu]Lu-PSMA-I&T was evaluated at a mild nephrotoxic risk of 4.5%."	"After binding to the PSMA receptor, [<sup>177</sup>Lu]Lu-PSMA-617 is internalized into the PSMA positive cells, resulting in a long retention within these cells; the high energy electrons emitted during the decay can selectively induce tissue and DNA damage, leading to cell death."
REF00243; REF00177	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	8.7 months	months	NCT03511664	.	Phase 3	"Of the 1003 patients who underwent scanning, 831 (82.9%) were judged to have met all the trial eligibility criteria, including the PSMA imaging criteria, and were randomly assigned, between June 4, 2018, and October 23, 2019, to receive either <sup>177</sup>Lu-PSMA-617 plus protocol-permitted standard care (551 patients) or standard care alone (280)."	.	.	.	.	.	.	PET/CT assay	"In an international phase III randomized controlled trial (VISION), men with PSMA positive mCRPC, previously treated with at least one ARAT and one or two taxane regimens, were randomly assigned in a 2 : 1 ratio to either <sup>177</sup>Lu-PSMA-617 for four to six cycles and protocol-permitted standard of care vs. standard of care therapy alone. The addition of Lu-PSMA-617 to a standard of care therapy improved the imaging-based PFS (8.7 vs. 3.4 months, hazard ratio: 0.40, 99% CI, 0.29-0.57) and OS (15.3 vs. 11.3 months, hazard ratio: 0.62, 95% CI: 0.52-0.74)."	"Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical like <sup>177</sup>Lu-PSMA-617, a beta particle emitter has demonstrated improvement in overall survival in mCRPC patients pretreated with ARAT or taxanes. Although immune checkpoint inhibitors are being tested in mCRPC, there is no robust evidence to support this premise."
REF00243; REF00177	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	15.3 months	months	NCT03511664	.	Phase 3	"Of the 1003 patients who underwent scanning, 831 (82.9%) were judged to have met all the trial eligibility criteria, including the PSMA imaging criteria, and were randomly assigned, between June 4, 2018, and October 23, 2019, to receive either <sup>177</sup>Lu-PSMA-617 plus protocol-permitted standard care (551 patients) or standard care alone (280)."	.	.	.	.	.	.	PET/CT assay	"In an international phase III randomized controlled trial (VISION), men with PSMA positive mCRPC, previously treated with at least one ARAT and one or two taxane regimens, were randomly assigned in a 2 : 1 ratio to either <sup>177</sup>Lu-PSMA-617 for four to six cycles and protocol-permitted standard of care vs. standard of care therapy alone. The addition of Lu-PSMA-617 to a standard of care therapy improved the imaging-based PFS (8.7 vs. 3.4 months, hazard ratio: 0.40, 99% CI, 0.29-0.57) and OS (15.3 vs. 11.3 months, hazard ratio: 0.62, 95% CI: 0.52-0.74)."	"Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical like <sup>177</sup>Lu-PSMA-617, a beta particle emitter has demonstrated improvement in overall survival in mCRPC patients pretreated with ARAT or taxanes. Although immune checkpoint inhibitors are being tested in mCRPC, there is no robust evidence to support this premise."
REF00243; REF00177	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Myelosuppression	47.40%	%	NCT03511664	.	Phase 3	"Of the 1003 patients who underwent scanning, 831 (82.9%) were judged to have met all the trial eligibility criteria, including the PSMA imaging criteria, and were randomly assigned, between June 4, 2018, and October 23, 2019, to receive either <sup>177</sup>Lu-PSMA-617 plus protocol-permitted standard care (551 patients) or standard care alone (280)."	.	.	.	.	.	.	PET/CT assay	"Myelosuppression was noted in 47.4% (grades 3-5 in 23.4%) patients in the Lu-PSMA-617 arm. Additional concerning toxicities included fatigue, xerostomia because of expression of PSMA in salivary glands, and nausea-vomiting."	"Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical like <sup>177</sup>Lu-PSMA-617, a beta particle emitter has demonstrated improvement in overall survival in mCRPC patients pretreated with ARAT or taxanes. Although immune checkpoint inhibitors are being tested in mCRPC, there is no robust evidence to support this premise."
REF00243; REF00177	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grades 3/5 myelosuppression	23.40%	%	NCT03511664	.	Phase 3	"Of the 1003 patients who underwent scanning, 831 (82.9%) were judged to have met all the trial eligibility criteria, including the PSMA imaging criteria, and were randomly assigned, between June 4, 2018, and October 23, 2019, to receive either <sup>177</sup>Lu-PSMA-617 plus protocol-permitted standard care (551 patients) or standard care alone (280)."	.	.	.	.	.	.	PET/CT assay	"Myelosuppression was noted in 47.4% (grades 3-5 in 23.4%) patients in the Lu-PSMA-617 arm. Additional concerning toxicities included fatigue, xerostomia because of expression of PSMA in salivary glands, and nausea-vomiting."	"Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical like <sup>177</sup>Lu-PSMA-617, a beta particle emitter has demonstrated improvement in overall survival in mCRPC patients pretreated with ARAT or taxanes. Although immune checkpoint inhibitors are being tested in mCRPC, there is no robust evidence to support this premise."
REF00245	PDC_00027	Midgut neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	13%	%	.	.	.	229 patients with midgut neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Hindgut neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	62%	%	.	.	.	14 patients with hindgut neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	43%	%	.	.	.	78 patients with pancreatic neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Bronchial neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	11%	%	.	.	.	21 patients with bronchial neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	PPGLa neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	0%	%	.	.	.	11 patients with PPGLa neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Unknown originb neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	35%	%	.	.	.	22 patients with unknown originb neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	21%	%	.	.	.	20 patients with others neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	22%	%	.	.	.	395 patients with neuroendocrine tumour.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Midgut neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	76%	%	.	.	.	229 patients with midgut neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Hindgut neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	31%	%	.	.	.	14 patients with hindgut neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	35%	%	.	.	.	78 patients with pancreatic neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Bronchial neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	63%	%	.	.	.	21 patients with bronchial neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	PPGLa neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	70%	%	.	.	.	11 patients with PPGLa neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Unknown originb neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	65%	%	.	.	.	22 patients with unknown originb neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	68%	%	.	.	.	20 patients with others neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	64%	%	.	.	.	395 patients with neuroendocrine tumour.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Midgut neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	11%	%	.	.	.	229 patients with midgut neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Hindgut neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	7%	%	.	.	.	14 patients with hindgut neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	22%	%	.	.	.	78 patients with pancreatic neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Bronchial neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	26%	%	.	.	.	21 patients with bronchial neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	PPGLa neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	30%	%	.	.	.	11 patients with PPGLa neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Unknown originb neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	0%	%	.	.	.	22 patients with unknown originb neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	11%	%	.	.	.	20 patients with others neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	14%	%	.	.	.	395 patients with neuroendocrine tumour.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Midgut neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	36 months	months	.	.	.	229 patients with midgut neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Hindgut neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	41 months	months	.	.	.	14 patients with hindgut neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	26 months	months	.	.	.	78 patients with pancreatic neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Bronchial neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	29 months	months	.	.	.	21 patients with bronchial neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	PPGLa neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	23 months	months	.	.	.	11 patients with PPGLa neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Unknown originb neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	35 months	months	.	.	.	22 patients with unknown originb neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	41 months	months	.	.	.	20 patients with others neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	33 months	months	.	.	.	395 patients with neuroendocrine tumour.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Midgut neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	47 months	months	.	.	.	229 patients with midgut neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Hindgut neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	50 months	months	.	.	.	14 patients with hindgut neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	50 months	months	.	.	.	78 patients with pancreatic neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Bronchial neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	59 months	months	.	.	.	21 patients with bronchial neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	PPGLa neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	44 months	months	.	.	.	11 patients with PPGLa neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Unknown originb neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	39 months	months	.	.	.	22 patients with unknown originb neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	39 months	months	.	.	.	20 patients with others neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	46 months	months	.	.	.	395 patients with neuroendocrine tumour.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	Computed tomography (CT) or magnetic resonance imaging (MRI) assay	"Of the 395 patients, 280 (71%) completed all four cycles, 28 patients (7%) completed three cycles, 54 patients (14%) completed two cycles and 33 patients (8%) completed one cycle. The estimated median PFS for the entire cohort (n = 395) was 33 months (95% CI, 29-37) with 227 (57%) of patients having PD by the end of the study (Figure 1). Mean Follow Up time was 41 months (95% CI, 37-45). The estimated median OS for the entire cohort (n = 395) was 46 months (95% CI, 48-56). The number of patients who had died by the end of the study was 192 (49%). The median OS in patients completing only one or two cycles (n = 87) was 13 months compared to 48 months for patients who had completed three or four cycles (n = 308). Reasons for not completing four cycles were radiological progression in 40 patients, toxicity in seven patients (2 due to extreme fatigue, 5 due to bone marrow toxicity), clinical deterioration in 31 patients, death in 26 patients and other reasons, including patient choice and loss to follow up, in 11 patients. The median OS for patients who had been treated with four cycles of <sup>177</sup>Lu-DOTATATE and were retreated with a further two cycles following PD (n = 26) was 59 months. Patients who had early PD (i.e., on the first response assessment cross-sectional study) following <sup>177</sup>Lu-DOTATATE had statistically significant worse OS; p-value <.001 (median OS 33 months)."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 anemia	38%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 leukopenia	8%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 thrombocytosis	18%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 lymphopenia	12%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 nephrotoxicity	9%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 anemia	9%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 leukopenia	9%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 thrombocytopenia	3%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 lymphopenia	25%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 2 nephrotoxicity	2%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 anemia	6%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 leukopenia	2%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 thrombocytopenia	1%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 lymphopenia	22%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 nephrotoxicity	0.60%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 anaemia	0%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 leukopenia	0.30%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 thrombocytopenia	0%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 lymphopenia	3%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00245	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 nephrotoxicity	0.30%	%	.	.	.	363 patients with neuroendocrine tumours.	.	.	.	.	4 cycles	Average activity of 7.477 GBq (SD &plusmn;0.02) per cycle	.	"Safety data was available in 363 patients. A total of 28 patients developed grade 3 or 4 bone marrow toxicity (8%) (excluding lymphopenia). Of these, 21 patients (6%) had anaemia, 10 patients (3%) had leukopenia and five patients (1%) had thrombocytopenia. In addition, grade 3 or 4 lymphopenia was recorded in 79 patients (22%) (Table 3). One patient (0.3%) developed grade 4 nephrotoxicity. This patient developed gradual decline in kidney function and was commenced on haemodialysis. The decline in kidney function was attributed to persistent vomiting with poor oral intake but a contributory role of PRRT cannot be excluded. This patient had a baseline eGFR of 39 ml/min/1.73 m2. No further grade 3/4 renal toxicities were encountered. Myelodysplastic disease (MDS) occurred in one patient (0.3%). This patient had undergone chemotherapy for diffuse large B cell lymphoma with chemotherapy (rituximab, cyclophosphamide, vincristine, prednisolone), followed by etoposide, methylprednisolone, cytarabine, cisplatin 6 months which resulted in a complete metabolic response. The patient's MDS was diagnosed 48 months after the start of chemotherapy and 17 months after commencing PRRT. No acute leukaemia occurred."	"In this single centre study of NET patients with generally moderate or large tumour burden, we found that <sup>177</sup>Lu-DOTATATE is an effective therapeutic modality for SSR expressing NETs. <sup>177</sup>Lu-DOTATATE resulted in DCR of 86% and median PFS and OS at 33 and 46 months, respectively. We found Ki-67, CgA and BMI to be independent predictive factors of PFS on multivariate analysis. <sup>177</sup>Lu-DOTATATE was generally well-tolerated, with grade 3 or 4 toxicity renal toxicity <1%, grade 3 or 4 bone marrow toxicity at 8% and MDS recorded in <1%."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	15.3 months	months	.	.	.	551 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks for up to a total of 6 doses	7.4 GBq (200 mCi)	.	"The co-primary endpoint of OS was statistically significant, with patients randomized to receive <sup>177</sup>Lu-PSMA-617 plus BSoC having prolonged OS (median estimate 15.3 months) compared to BSoC alone (median estimate 11.3 months), hazard ratio (HR) 0.62 (95% CI: 0.52, 0.74, p<0.001). The planned interim OS analysis was not necessary as the targeted number of OS events were observed before the targeted number of rPFS events. Therefore, the final OS analysis was evaluated at the time of rPFS analysis."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median radiographic progression-free survival (rPFS)	8.7 months	months	.	.	.	385 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks for up to a total of 6 doses	7.4 GBq (200 mCi)	.	"The co-primary endpoint of OS was statistically significant, with patients randomized to receive <sup>177</sup>Lu-PSMA-617 plus BSoC having prolonged OS (median estimate 15.3 months) compared to BSoC alone (median estimate 11.3 months), hazard ratio (HR) 0.62 (95% CI: 0.52, 0.74, p<0.001). The planned interim OS analysis was not necessary as the targeted number of OS events were observed before the targeted number of rPFS events. Therefore, the final OS analysis was evaluated at the time of rPFS analysis."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median objective response rate (mORR)	30%	%	.	.	.	319 patients with metastatic castration-resistant prostate cancer who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6weeks interval.	.	.	.	.	Every 6 weeks for up to a total of 6 doses	7.4 GBq (200 mCi)	.	"The co-primary endpoint of OS was statistically significant, with patients randomized to receive <sup>177</sup>Lu-PSMA-617 plus BSoC having prolonged OS (median estimate 15.3 months) compared to BSoC alone (median estimate 11.3 months), hazard ratio (HR) 0.62 (95% CI: 0.52, 0.74, p<0.001). The planned interim OS analysis was not necessary as the targeted number of OS events were observed before the targeted number of rPFS events. Therefore, the final OS analysis was evaluated at the time of rPFS analysis."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	6%	%	.	.	.	319 patients with metastatic castration-resistant prostate cancer who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6weeks interval.	.	.	.	.	Every 6 weeks for up to a total of 6 doses	7.4 GBq (200 mCi)	.	"The co-primary endpoint of OS was statistically significant, with patients randomized to receive <sup>177</sup>Lu-PSMA-617 plus BSoC having prolonged OS (median estimate 15.3 months) compared to BSoC alone (median estimate 11.3 months), hazard ratio (HR) 0.62 (95% CI: 0.52, 0.74, p<0.001). The planned interim OS analysis was not necessary as the targeted number of OS events were observed before the targeted number of rPFS events. Therefore, the final OS analysis was evaluated at the time of rPFS analysis."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	24%	%	.	.	.	319 patients with metastatic castration-resistant prostate cancer who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6weeks interval.	.	.	.	.	Every 6 weeks for up to a total of 6 doses	7.4 GBq (200 mCi)	.	"The co-primary endpoint of OS was statistically significant, with patients randomized to receive <sup>177</sup>Lu-PSMA-617 plus BSoC having prolonged OS (median estimate 15.3 months) compared to BSoC alone (median estimate 11.3 months), hazard ratio (HR) 0.62 (95% CI: 0.52, 0.74, p<0.001). The planned interim OS analysis was not necessary as the targeted number of OS events were observed before the targeted number of rPFS events. Therefore, the final OS analysis was evaluated at the time of rPFS analysis."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Sepsis	0.90%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Pancytopenia	0.60%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Hepatic failure	0.40%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Rate of intracranial hemorrhage	0.20%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Subdural hematoma	0.20%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Rate of ischemic stroke	0.20%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Aspiration pneumonia	0.20%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Fatigue	20%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Xerostomia rate	20%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Nausea	20%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Anemia	20%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Appetite decrease rate	20%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Constipation	20%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Lymphocytes decrease rate	30%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Hemoglobin decrease rate	30%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Leukocytes decrease	30%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Platelets decrease rate	30%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Calcium decrease rate	30%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00246	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Sodium decrease rate	30%	%	.	.	.	734 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 doses (range: 1 to 6)	"Median cumulative dose 37.5 GBq (range, 7.0 to 48.3)"	.	"Serious adverse reactions occurred in 36% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC. Fatal adverse reactions occurred in 2.8% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC, including sepsis (0.9%), pancytopenia (0.6%), hepatic failure (0.4%), intracranial hemorrhage (0.2%), subdural hematoma (0.2%), ischemic stroke (0.2%), COVID-19 (0.2%), and aspiration pneumonia (0.2%). The 2 fatal adverse reactions of intracranial hemorrhage and subdural hematoma occurred in patients who had concurrent treatment-related thrombocytopenia. The most common adverse reactions (&ge; 20%) occurring at a higher incidence in patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in &ge; 30% of patients who received <sup>177</sup>Lu-PSMA-617 plus BSoC were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium."	"On March 23, 2022, the FDA approved <sup>177</sup>Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The approval was based on a meaningful advantage in overall survival supported by a delay in tumor progression and higher objective response rate. The decision took into account several important factors unique to this applications context. Metastatic castration-resistant prostate cancer (mCRPC) is a life-threatening condition that lacks curative treatment, creating an unmet need. This product provides a novel mechanism of action as the first radioligand therapeutic agent for mCRPC providing anti-tumor effects in both bone and non-bone sites and may provide an opportunity to be combined with other available therapies with different toxicity profiles across mechanistic classes. Finally, <sup>177</sup>Lu-PSMA-617 offers a different safety profile than other available systemic therapies which was determined to be acceptable for the indicated patient population, expanding treatment options that can be individualized to a patients preferences and comorbidities."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019.	Identified from the Human Clinical Data	High Expreesion	Median percentage decrease in PSA	-19.80%	%	.	.	.	.	.	.	.	.	1 cycles	7081 MBq (IQR 6995-7188)	18F/68Ga-PSMA PET/CT assay	"The median percentage decrease in PSA (all patients) was -19.8% (IQR -37.1-4.3) after the first treatment, -42.9% (IQR -69.8-16.5) after the second treatment and -70.4% (IQR -88.6--35.1) after the third treatment. A trend towards a greater PSA decrease with a greater number of treatment cycles was also observed in patients who received more than three treatment cycles. For example, the median decrease in PSA was -94.2% (IQRT -91.0--35.6) for patients who received six treatment cycles (n = 10). Altogether, there were six patients (10%) with an exceptional (more than 98%) PSA treatment response. The best response was a 99.9% PSA decrease, which represented a change from 121 to 0.1 ng/L. All of the patients with an excellent treatment response had detectable PSA levels after PSMA-RLT. In general, the PSA response was not associated with Gleason score, pre-treatment PSA kinetics, MTV, TLA, SUVmax values or lesion diameters."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019.	Identified from the Human Clinical Data	High Expreesion	Median percentage decrease in PSA	-42.90%	%	.	.	.	.	.	.	.	.	2 cycles	7081 MBq (IQR 6995-7188)	18F/68Ga-PSMA PET/CT assay	"The median percentage decrease in PSA (all patients) was -19.8% (IQR -37.1-4.3) after the first treatment, -42.9% (IQR -69.8-16.5) after the second treatment and -70.4% (IQR -88.6--35.1) after the third treatment. A trend towards a greater PSA decrease with a greater number of treatment cycles was also observed in patients who received more than three treatment cycles. For example, the median decrease in PSA was -94.2% (IQRT -91.0--35.6) for patients who received six treatment cycles (n = 10). Altogether, there were six patients (10%) with an exceptional (more than 98%) PSA treatment response. The best response was a 99.9% PSA decrease, which represented a change from 121 to 0.1 ng/L. All of the patients with an excellent treatment response had detectable PSA levels after PSMA-RLT. In general, the PSA response was not associated with Gleason score, pre-treatment PSA kinetics, MTV, TLA, SUVmax values or lesion diameters."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019.	Identified from the Human Clinical Data	High Expreesion	Median percentage decrease in PSA	-70.40%	%	.	.	.	.	.	.	.	.	3 cycles	7081 MBq (IQR 6995-7188)	18F/68Ga-PSMA PET/CT assay	"The median percentage decrease in PSA (all patients) was -19.8% (IQR -37.1-4.3) after the first treatment, -42.9% (IQR -69.8-16.5) after the second treatment and -70.4% (IQR -88.6--35.1) after the third treatment. A trend towards a greater PSA decrease with a greater number of treatment cycles was also observed in patients who received more than three treatment cycles. For example, the median decrease in PSA was -94.2% (IQRT -91.0--35.6) for patients who received six treatment cycles (n = 10). Altogether, there were six patients (10%) with an exceptional (more than 98%) PSA treatment response. The best response was a 99.9% PSA decrease, which represented a change from 121 to 0.1 ng/L. All of the patients with an excellent treatment response had detectable PSA levels after PSMA-RLT. In general, the PSA response was not associated with Gleason score, pre-treatment PSA kinetics, MTV, TLA, SUVmax values or lesion diameters."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019.	Identified from the Human Clinical Data	High Expreesion	Median percentage decrease in PSA	-94.20%	%	.	.	.	.	.	.	.	.	6 cycles	7081 MBq (IQR 6995-7188)	18F/68Ga-PSMA PET/CT assay	"The median percentage decrease in PSA (all patients) was -19.8% (IQR -37.1-4.3) after the first treatment, -42.9% (IQR -69.8-16.5) after the second treatment and -70.4% (IQR -88.6--35.1) after the third treatment. A trend towards a greater PSA decrease with a greater number of treatment cycles was also observed in patients who received more than three treatment cycles. For example, the median decrease in PSA was -94.2% (IQRT -91.0--35.6) for patients who received six treatment cycles (n = 10). Altogether, there were six patients (10%) with an exceptional (more than 98%) PSA treatment response. The best response was a 99.9% PSA decrease, which represented a change from 121 to 0.1 ng/L. All of the patients with an excellent treatment response had detectable PSA levels after PSMA-RLT. In general, the PSA response was not associated with Gleason score, pre-treatment PSA kinetics, MTV, TLA, SUVmax values or lesion diameters."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	0.4 year	year	.	.	.	.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	18F/68Ga-PSMA PET/CT assay	"The median follow-up time was 1.7 years (y; IQR 0.7-2.2). The median PSA progression-free survival was 0.4 y (IQR 0.2-0.8) and the OS was 1.6 y (IQR 0.7-2.2). During follow-up, 36 (58%) patients died. The survival probability was significantly better among patients with significant (>50%) PSA response compared to non-responders, p < 0.04."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	1.6 years	years	.	.	.	.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	18F/68Ga-PSMA PET/CT assay	"The median follow-up time was 1.7 years (y; IQR 0.7-2.2). The median PSA progression-free survival was 0.4 y (IQR 0.2-0.8) and the OS was 1.6 y (IQR 0.7-2.2). During follow-up, 36 (58%) patients died. The survival probability was significantly better among patients with significant (>50%) PSA response compared to non-responders, p < 0.04."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 hemoglobin	91.90%	%	.	.	.	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019. Grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	.	"In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to <sup>177</sup>Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 leucopenia	21.00%	%	.	.	.	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019. Grade 1-2 leucopenia was observed in thirteen patients.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	.	"In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to <sup>177</sup>Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 leucopenia	3.20%	%	.	.	.	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019. Two patients had grade 3 leucopenia.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	.	"In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to <sup>177</sup>Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 thrombocytopenia	27.40%	%	.	.	.	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019. Only one patient had grade 3 trombocytopenia.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	.	"In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to <sup>177</sup>Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 thrombocytopenia	1.60%	%	.	.	.	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019. Grade 1-2 thrombocytopenia was observed in seventeen patients.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	.	"In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to <sup>177</sup>Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019. Grade 3 tiredness was reported by ten (16.1%).	Identified from the Human Clinical Data	High Expreesion	Grade 3 tiredness	16.10%	%	.	.	.	.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	.	"In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to <sup>177</sup>Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 tiredness	43.50%	%	.	.	.	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019. Grade 1-2 tiredness by twenty-seven (43.5%) of the patients.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	.	"In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to <sup>177</sup>Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019. Grade 3 pain was reported by four subjects (6.5%).	Identified from the Human Clinical Data	High Expreesion	Grade 3 pain	6.50%	%	.	.	.	.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	.	"In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to <sup>177</sup>Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019. Grade 3 infection was reported by two subjects.	Identified from the Human Clinical Data	High Expreesion	Grade 3 infection	3.20%	%	.	.	.	.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	.	"In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to <sup>177</sup>Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 xerostomia	53.20%	%	.	.	.	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	.	"In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to <sup>177</sup>Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	This is a single-center retrospective analysis in 62 men with pathologically confirmed castration resistant metastatic prostate cancer who were treated with <sup>177</sup>Lu-PSMA-617 during January 2017-February 2019. Grade 1-2 nausea was reported by twenty-two (35.5%).	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 nausea	35.50%	%	.	.	.	.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	.	"In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to <sup>177</sup>Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00247	PDC_00029	Metastatic castration-resistant prostate cancer	62 men with pathologically confirmed castration resistant metastatic prostate cancer.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 diarrhea	25.80%	%	.	.	.	.	.	.	.	.	1-7 cycles	7081 MBq (IQR 6995-7188)	.	"In this patient cohort, grade 1-2 hemoglobin values were observed in 57 (91.9%) patients after treatment, but there were no grade 3 hemoglobin values. Grade 1-2 leucopenia was observed in thirteen patients and two patients had grade 3 leucopenia. Grade 1-2 thrombocytopenia was observed in seventeen patients and only one patient had grade 3 trombocytopenia. Tiredness appeared to be the most serious patient-reported adverse event during treatment. Grade 3 tiredness was reported by ten (16.1%) and grade 1-2 tiredness by twenty-seven (43.5%) of the patients. Grade 3 pain was reported by four subjects (6.5%) and grade 3 infection was reported by two subjects. None of the grade 3 pain or infections were related to <sup>177</sup>Lu-PSMA-617 treatment. Grade 1-2 dryness of the mouth was reported by thirty-three (53.2%) of the patients. Grade 1-2 nausea was reported by twenty-two (35.5%) and diarrhea by sixteen (25.8%) of the patients. Grade 4-5 side effects were not reported at all."	"<sup>177</sup>Lu-PSMA-RLT in a four-week interval with a fixed dose was safe and effective. A significant PSA response was observed in six out of ten patients, which was also associated with better OS and PFS. A shorter treatment interval may broaden the therapeutic window among mCRPC patients with high volume disease and rapidly rising PSA. Pre-treatment staging PSMA was not helpful in distinguishing responders from non-responders. However, parameters for tumor burden and its activity provide prognostic information related to OS and PFS."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	70%	%	.	.	.	10 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	8 weeks	.	.	"Though the first experience with PSMA-targeted <sup>177</sup>Lu dates to 2013 at Bad Burka, this experience was not reported until later. The first report on safety and efficacy came from investigators at University Hospital Bonn and University Hospital Muenster. The authors retrospectively evaluated the results of 10 consecutive patients with mCRPC who were treated with a single dose of <sup>177</sup>Lu-DKFZ-617 (later called simply PSMA-617) PSMA between 2013 and 2014. They showed that after 8 weeks, 7 patients (70%) showed a PSA decline with 5 patients (50%) having more than a 50% decline in PSA. Grade 3 or higher hematotoxicity was seen in only one patient and there was no relevant nephrotoxicity or hepatotoxicity."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	50.00%	%	.	.	.	10 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	8 weeks	.	.	"Though the first experience with PSMA-targeted <sup>177</sup>Lu dates to 2013 at Bad Burka, this experience was not reported until later. The first report on safety and efficacy came from investigators at University Hospital Bonn and University Hospital Muenster. The authors retrospectively evaluated the results of 10 consecutive patients with mCRPC who were treated with a single dose of <sup>177</sup>Lu-DKFZ-617 (later called simply PSMA-617) PSMA between 2013 and 2014. They showed that after 8 weeks, 7 patients (70%) showed a PSA decline with 5 patients (50%) having more than a 50% decline in PSA. Grade 3 or higher hematotoxicity was seen in only one patient and there was no relevant nephrotoxicity or hepatotoxicity."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 hematotoxicity	10%	%	.	.	.	10 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	8 weeks	.	.	"Though the first experience with PSMA-targeted <sup>177</sup>Lu dates to 2013 at Bad Burka, this experience was not reported until later. The first report on safety and efficacy came from investigators at University Hospital Bonn and University Hospital Muenster. The authors retrospectively evaluated the results of 10 consecutive patients with mCRPC who were treated with a single dose of <sup>177</sup>Lu-DKFZ-617 (later called simply PSMA-617) PSMA between 2013 and 2014. They showed that after 8 weeks, 7 patients (70%) showed a PSA decline with 5 patients (50%) having more than a 50% decline in PSA. Grade 3 or higher hematotoxicity was seen in only one patient and there was no relevant nephrotoxicity or hepatotoxicity."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	59%	%	.	.	.	28 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 dose	.	.	"A subsequent retrospective study, the first evaluating multiple administrations of <sup>177</sup>Lu-PSMA-617, was reported by the same group. The authors reviewed 28 consecutive patients who received 50 infusions of <sup>177</sup>Lu-PSMA-617 between 2014 and 2015. In their report, a PSA decline was noted in 59% and 75% of patients after 1 and 2 therapies, respectively, and a PSA decline of 50% or greater occurred in 32% and 50%, respectively. The estimated median survival was 29.4 weeks compared to 19.7 weeks in the historical best supportive care group which was statistically significant (HR 44; 95% CI 0.20-0.95; P=.031). Authors of the study also noted no significant changes in hematologic or renal parameters"	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	75%	%	.	.	.	28 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 doses	.	.	"A subsequent retrospective study, the first evaluating multiple administrations of <sup>177</sup>Lu-PSMA-617, was reported by the same group. The authors reviewed 28 consecutive patients who received 50 infusions of <sup>177</sup>Lu-PSMA-617 between 2014 and 2015. In their report, a PSA decline was noted in 59% and 75% of patients after 1 and 2 therapies, respectively, and a PSA decline of 50% or greater occurred in 32% and 50%, respectively. The estimated median survival was 29.4 weeks compared to 19.7 weeks in the historical best supportive care group which was statistically significant (HR 44; 95% CI 0.20-0.95; P=.031). Authors of the study also noted no significant changes in hematologic or renal parameters"	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	32.00%	%	.	.	.	28 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 dose	.	.	"A subsequent retrospective study, the first evaluating multiple administrations of <sup>177</sup>Lu-PSMA-617, was reported by the same group. The authors reviewed 28 consecutive patients who received 50 infusions of <sup>177</sup>Lu-PSMA-617 between 2014 and 2015. In their report, a PSA decline was noted in 59% and 75% of patients after 1 and 2 therapies, respectively, and a PSA decline of 50% or greater occurred in 32% and 50%, respectively. The estimated median survival was 29.4 weeks compared to 19.7 weeks in the historical best supportive care group which was statistically significant (HR 44; 95% CI 0.20-0.95; P=.031). Authors of the study also noted no significant changes in hematologic or renal parameters"	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	50.00%	%	.	.	.	28 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 doses	.	.	"A subsequent retrospective study, the first evaluating multiple administrations of <sup>177</sup>Lu-PSMA-617, was reported by the same group. The authors reviewed 28 consecutive patients who received 50 infusions of <sup>177</sup>Lu-PSMA-617 between 2014 and 2015. In their report, a PSA decline was noted in 59% and 75% of patients after 1 and 2 therapies, respectively, and a PSA decline of 50% or greater occurred in 32% and 50%, respectively. The estimated median survival was 29.4 weeks compared to 19.7 weeks in the historical best supportive care group which was statistically significant (HR 44; 95% CI 0.20-0.95; P=.031). Authors of the study also noted no significant changes in hematologic or renal parameters"	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median survival time	29.4 weeks	weeks	.	.	.	28 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-6 doses	.	.	"A subsequent retrospective study, the first evaluating multiple administrations of <sup>177</sup>Lu-PSMA-617, was reported by the same group. The authors reviewed 28 consecutive patients who received 50 infusions of <sup>177</sup>Lu-PSMA-617 between 2014 and 2015. In their report, a PSA decline was noted in 59% and 75% of patients after 1 and 2 therapies, respectively, and a PSA decline of 50% or greater occurred in 32% and 50%, respectively. The estimated median survival was 29.4 weeks compared to 19.7 weeks in the historical best supportive care group which was statistically significant (HR 44; 95% CI 0.20-0.95; P=.031). Authors of the study also noted no significant changes in hematologic or renal parameters"	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 3/4 hematotoxicity	12%	%	.	.	.	145 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-4 cycles	.	.	"A larger retrospective multicenter analysis of 145 patients treated with 248 therapy cycles of <sup>177</sup>Lu-PSMA-617 at 12 nuclear medicine centers throughout Germany between 2014 and 2015 was conducted. Patients had received 1-4 therapy cycles of treatment. In their analysis, the biochemical response rate (defined as a 50% or greater drop in PSA) was 45% after all therapy cycles. Grade 3 or 4 hematotoxicity occurred in 18 patients (12%) and xerostomia occurred in 11 patients (8%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Xerostomia	8%	%	.	.	.	145 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-4 cycles	.	.	"A larger retrospective multicenter analysis of 145 patients treated with 248 therapy cycles of <sup>177</sup>Lu-PSMA-617 at 12 nuclear medicine centers throughout Germany between 2014 and 2015 was conducted. Patients had received 1-4 therapy cycles of treatment. In their analysis, the biochemical response rate (defined as a 50% or greater drop in PSA) was 45% after all therapy cycles. Grade 3 or 4 hematotoxicity occurred in 18 patients (12%) and xerostomia occurred in 11 patients (8%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	57.00%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6weeks interval.	.	.	.	.	4 cycles at 6-week intervals	.	.	"Thirty patients received treatment in this study out of 43 screened patients, thus only 70% of patients were treated. A PSA response was seen in 17 patients (57%). There were no treatment-related deaths in the study and the most common AEs were grade 1 dry mouth in 26 patients (87%), grade 1-2 nausea in 15 patients (50%), and grade 1-2 fatigue in 15 patients (50%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1 xerostomia rate	87%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6weeks interval.	.	.	.	.	4 cycles at 6-week intervals	.	.	"Thirty patients received treatment in this study out of 43 screened patients, thus only 70% of patients were treated. A PSA response was seen in 17 patients (57%). There were no treatment-related deaths in the study and the most common AEs were grade 1 dry mouth in 26 patients (87%), grade 1-2 nausea in 15 patients (50%), and grade 1-2 fatigue in 15 patients (50%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 nausea	50%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6weeks interval.	.	.	.	.	4 cycles at 6-week intervals	.	.	"Thirty patients received treatment in this study out of 43 screened patients, thus only 70% of patients were treated. A PSA response was seen in 17 patients (57%). There were no treatment-related deaths in the study and the most common AEs were grade 1 dry mouth in 26 patients (87%), grade 1-2 nausea in 15 patients (50%), and grade 1-2 fatigue in 15 patients (50%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 fatigue	50%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6weeks interval.	.	.	.	.	4 cycles at 6-week intervals	.	.	"Thirty patients received treatment in this study out of 43 screened patients, thus only 70% of patients were treated. A PSA response was seen in 17 patients (57%). There were no treatment-related deaths in the study and the most common AEs were grade 1 dry mouth in 26 patients (87%), grade 1-2 nausea in 15 patients (50%), and grade 1-2 fatigue in 15 patients (50%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	15.3 months	months	.	.	.	831 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks for 4-6 cycles	.	PSMA PET assay	"Investigators found that patients who received <sup>177</sup>Lu-PSMA-617 had a statistically significant improvement in overall survival with a median survival of 15.3 months vs. 11.3 months (HR for death 0.62, 95% CI 0.52-0.74, P<.001). Radiographic progression-free survival (rPFS) also improved and favored <sup>177</sup>Lu-PSMA-617. Key secondary endpoints including time to the first symptomatic skeletal event or death, complete responses based on RECIST 1.1, confirmed decreases in PSA, time to deterioration in the FACT-P total score, and BPI-SF pain intensity score, all favored <sup>177</sup>Lu-PSMA-617."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Fatigue	43%	%	.	.	.	831 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks for 4-6 cycles	.	.	"Toxicities of grade 3 or higher were experienced by 52.7% of patients. The most common all-grade toxicities with <sup>177</sup>Lu-PSMA-617 were fatigue (43.1%), dry mouth (38.8%-0% grade 3 or higher), and nausea (35.3%). The most common grade 3 or higher toxicities included anemia (12.9%), thrombocytopenia (7.9%), and leucopenia (7.8%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 xerostomia rate	0% - 38.8%	%	.	.	.	831 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks for 4-6 cycles	.	.	"Toxicities of grade 3 or higher were experienced by 52.7% of patients. The most common all-grade toxicities with <sup>177</sup>Lu-PSMA-617 were fatigue (43.1%), dry mouth (38.8%-0% grade 3 or higher), and nausea (35.3%). The most common grade 3 or higher toxicities included anemia (12.9%), thrombocytopenia (7.9%), and leucopenia (7.8%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Nausea	35%	%	.	.	.	831 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks for 4-6 cycles	.	.	"Toxicities of grade 3 or higher were experienced by 52.7% of patients. The most common all-grade toxicities with <sup>177</sup>Lu-PSMA-617 were fatigue (43.1%), dry mouth (38.8%-0% grade 3 or higher), and nausea (35.3%). The most common grade 3 or higher toxicities included anemia (12.9%), thrombocytopenia (7.9%), and leucopenia (7.8%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 anemia	13%	%	.	.	.	831 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks for 4-6 cycles	.	.	"Toxicities of grade 3 or higher were experienced by 52.7% of patients. The most common all-grade toxicities with <sup>177</sup>Lu-PSMA-617 were fatigue (43.1%), dry mouth (38.8%-0% grade 3 or higher), and nausea (35.3%). The most common grade 3 or higher toxicities included anemia (12.9%), thrombocytopenia (7.9%), and leucopenia (7.8%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	8%	%	.	.	.	831 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks for 4-6 cycles	.	.	"Toxicities of grade 3 or higher were experienced by 52.7% of patients. The most common all-grade toxicities with <sup>177</sup>Lu-PSMA-617 were fatigue (43.1%), dry mouth (38.8%-0% grade 3 or higher), and nausea (35.3%). The most common grade 3 or higher toxicities included anemia (12.9%), thrombocytopenia (7.9%), and leucopenia (7.8%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 leucopenia	8%	%	.	.	.	831 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks for 4-6 cycles	.	.	"Toxicities of grade 3 or higher were experienced by 52.7% of patients. The most common all-grade toxicities with <sup>177</sup>Lu-PSMA-617 were fatigue (43.1%), dry mouth (38.8%-0% grade 3 or higher), and nausea (35.3%). The most common grade 3 or higher toxicities included anemia (12.9%), thrombocytopenia (7.9%), and leucopenia (7.8%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	66.00%	%	.	.	.	200 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks (up to 6 cycles)	.	68Ga-PSMA PET assay	"Of the patients with PET screening in TheraP, approximately 27% were excluded from treatment. Investigators found that patients who received <sup>177</sup>Lu-PSMA-617 were more likely to receive a PSA response (66% vs. 37% in the intent-to-treat group, P<.0001). Updated survival analysis was presented at a 2022 meeting, and overall survival was similar between <sup>177</sup>Lu-PSMA-617 and cabazitaxel at 19.1 months versus 19.6 months was not significantly different between the 2 arms. The finding of survival equivalence in a PSMA-selected patient population was surprising to some but it is well known that cabazitaxel is an important life-prolonging therapy in mCRPC."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	19.1 months	months	.	.	.	200 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks (up to 6 cycles)	.	68Ga-PSMA PET assay	"Of the patients with PET screening in TheraP, approximately 27% were excluded from treatment. Investigators found that patients who received <sup>177</sup>Lu-PSMA-617 were more likely to receive a PSA response (66% vs. 37% in the intent-to-treat group, P<.0001). Updated survival analysis was presented at a 2022 meeting, and overall survival was similar between <sup>177</sup>Lu-PSMA-617 and cabazitaxel at 19.1 months versus 19.6 months was not significantly different between the 2 arms. The finding of survival equivalence in a PSMA-selected patient population was surprising to some but it is well known that cabazitaxel is an important life-prolonging therapy in mCRPC."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 3/4 adverse events	33%	%	.	.	.	200 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks (up to 6 cycles)	.	.	"Grade 3-4 AEs occurred in 32 (33%) of men who received <sup>177</sup>Lu-PSMA-617 versus 45 (53%) of men in the cabazitaxel group. All-grade toxicities that were more common in the <sup>177</sup>Lu-PSMA-617 were dry mouth (60% vs. 21%), dry eyes (30% vs. 4%), and thrombocytopenia (18% vs. 5%). All-grade toxicities that were more common with cabazitaxel were diarrhea (52% vs. 18%), neuropathy (26% vs. 10%), and dysgeusia (27% vs. 12%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Xerostomia rate	60%	%	.	.	.	200 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks (up to 6 cycles)	.	.	"Grade 3-4 AEs occurred in 32 (33%) of men who received <sup>177</sup>Lu-PSMA-617 versus 45 (53%) of men in the cabazitaxel group. All-grade toxicities that were more common in the <sup>177</sup>Lu-PSMA-617 were dry mouth (60% vs. 21%), dry eyes (30% vs. 4%), and thrombocytopenia (18% vs. 5%). All-grade toxicities that were more common with cabazitaxel were diarrhea (52% vs. 18%), neuropathy (26% vs. 10%), and dysgeusia (27% vs. 12%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Xerophthalmia rate	30%	%	.	.	.	200 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks (up to 6 cycles)	.	.	"Grade 3-4 AEs occurred in 32 (33%) of men who received <sup>177</sup>Lu-PSMA-617 versus 45 (53%) of men in the cabazitaxel group. All-grade toxicities that were more common in the <sup>177</sup>Lu-PSMA-617 were dry mouth (60% vs. 21%), dry eyes (30% vs. 4%), and thrombocytopenia (18% vs. 5%). All-grade toxicities that were more common with cabazitaxel were diarrhea (52% vs. 18%), neuropathy (26% vs. 10%), and dysgeusia (27% vs. 12%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	18%	%	.	.	.	200 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks (up to 6 cycles)	.	.	"Grade 3-4 AEs occurred in 32 (33%) of men who received <sup>177</sup>Lu-PSMA-617 versus 45 (53%) of men in the cabazitaxel group. All-grade toxicities that were more common in the <sup>177</sup>Lu-PSMA-617 were dry mouth (60% vs. 21%), dry eyes (30% vs. 4%), and thrombocytopenia (18% vs. 5%). All-grade toxicities that were more common with cabazitaxel were diarrhea (52% vs. 18%), neuropathy (26% vs. 10%), and dysgeusia (27% vs. 12%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Diarrhea	52%	%	.	.	.	200 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks (up to 6 cycles)	.	.	"Grade 3-4 AEs occurred in 32 (33%) of men who received <sup>177</sup>Lu-PSMA-617 versus 45 (53%) of men in the cabazitaxel group. All-grade toxicities that were more common in the <sup>177</sup>Lu-PSMA-617 were dry mouth (60% vs. 21%), dry eyes (30% vs. 4%), and thrombocytopenia (18% vs. 5%). All-grade toxicities that were more common with cabazitaxel were diarrhea (52% vs. 18%), neuropathy (26% vs. 10%), and dysgeusia (27% vs. 12%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Neuropathy	26%	%	.	.	.	200 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks (up to 6 cycles)	.	.	"Grade 3-4 AEs occurred in 32 (33%) of men who received <sup>177</sup>Lu-PSMA-617 versus 45 (53%) of men in the cabazitaxel group. All-grade toxicities that were more common in the <sup>177</sup>Lu-PSMA-617 were dry mouth (60% vs. 21%), dry eyes (30% vs. 4%), and thrombocytopenia (18% vs. 5%). All-grade toxicities that were more common with cabazitaxel were diarrhea (52% vs. 18%), neuropathy (26% vs. 10%), and dysgeusia (27% vs. 12%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00248	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Dysgeusia	27%	%	.	.	.	200 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6 weeks (up to 6 cycles)	.	.	"Grade 3-4 AEs occurred in 32 (33%) of men who received <sup>177</sup>Lu-PSMA-617 versus 45 (53%) of men in the cabazitaxel group. All-grade toxicities that were more common in the <sup>177</sup>Lu-PSMA-617 were dry mouth (60% vs. 21%), dry eyes (30% vs. 4%), and thrombocytopenia (18% vs. 5%). All-grade toxicities that were more common with cabazitaxel were diarrhea (52% vs. 18%), neuropathy (26% vs. 10%), and dysgeusia (27% vs. 12%)."	"Radiopharmaceuticals have been used in prostate cancer for decades with known efficacy in palliation of bone metastasis. The FDA approval of the most recent radiopharmaceutical, <sup>177</sup>Lu-PSMA-617, shows a clear overall survival benefit compared to the best SOC. Current studies are ongoing to evaluate the effectiveness of <sup>177</sup>Lu-PSMA-617 in earlier lines of therapy, such as after only 1 line of therapy with an ARPI as in the PSMAfore study, or in mCSPC in combination with ADT and an ARPI as in the PSMAddition study. Studies are also ongoing with <sup>177</sup>Lu-PSMA-617 in combination with other treatments which may produce a synergistic effect. As described, there are many clinical trials ongoing that are modifying the <sup>177</sup>Lu-PSMA-617 to possibly achieve improved results. Studies are also ongoing looking at swapping the <sup>177</sup>Lu for another radioactive agent, such as 225Ac (an alpha emitter) which may have benefits over the beta-emitting <sup>177</sup>Lu. Other studies are looking at J591, a monoclonal antibody to PSMA which has unique differences compared to small-molecule PSMA binders. Overall, PSMA-based radioligand therapy has been shown to be an effective and life-prolonging therapy and should be considered a treatment option for selected men with mCRPC. As described, there are many ongoing studies further evaluating PSMA radioligand therapy in Australia, South Africa, Europe, and the United States, representing a truly global effort to improve prostate cancer care."
REF00249	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	55 &plusmn; 2 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	2 h	10 MBq/nmol (3.75 nM)	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	68 &plusmn; 5 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	4 h	10 MBq/nmol (3.75 nM)	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	15 &plusmn; 1 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	2 h	10 MBq/nmol (3.75 nM)	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	20 &plusmn; 3 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	4 h	10 MBq/nmol (3.75 nM)	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00026	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	57 &plusmn; 5 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	2 h	3.75 nM	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00026	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	69 &plusmn; 6 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	4 h	3.75 nM	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00026	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	15 &plusmn; 1 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	2 h	3.75 nM	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00026	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	22 &plusmn; 3 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	4 h	3.75 nM	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	0.10%	%	.	.	.	.	Prostate carcinoma	PSMA-negative PC-3 flu cell	.	.	4 h	10 MBq/nmol (3.75 nM)	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00026	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	0.10%	%	.	.	.	.	Prostate carcinoma	PSMA-negative PC-3 flu cell	.	.	4 h	3.75 nM	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	11 &plusmn; 1 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	2 h	10 MBq/nmol (3.75 nM)	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	14 &plusmn; 1 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	4 h	10 MBq/nmol (3.75 nM)	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	6.4 &plusmn; 0.6 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	2 h	10 MBq/nmol (3.75 nM)	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	10 &plusmn; 2 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	4 h	10 MBq/nmol (3.75 nM)	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell blocking rate	0.10%	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	2 h	10 MBq/nmol (3.75 nM)	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell blocking rate	0.20%	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	4 h	10 MBq/nmol (3.75 nM)	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00026	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	13 &plusmn; 2 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	2 h	3.75 nM	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00026	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	18 &plusmn; 2 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	4 h	3.75 nM	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00026	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	8.3 &plusmn; 1.4 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	2 h	3.75 nM	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00026	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	13 &plusmn; 2 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	4 h	3.75 nM	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00026	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell blocking rate	0.50%	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	2 h	3.75 nM	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00026	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell blocking rate	0.50%	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	4 h	3.75 nM	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00025	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	47 &plusmn; 3 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	2 h	50 MBq/nmol (0.75 nM)	ICP-MS or &gamma;-counting	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00025	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	54 &plusmn; 6 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	4 h	50 MBq/nmol (0.75 nM)	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00025	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	8.2 &plusmn; 1.0 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	2 h	50 MBq/nmol (0.75 nM)	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00025	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	11 &plusmn; 3 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	4 h	50 MBq/nmol (0.75 nM)	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00024	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	51 &plusmn; 4 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	2 h	0.75 nM	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00024	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	60 &plusmn; 5 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	4 h	0.75 nM	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00024	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	13 &plusmn; 1 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	2 h	0.75 nM	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00024	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	17 &plusmn; 1 %	%	.	.	.	.	Prostate carcinoma	PSMA-positive PC-3 PIP cell	.	.	4 h	0.75 nM	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00025	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	0.10%	%	.	.	.	.	Prostate carcinoma	PSMA-negative PC-3 flu cell	.	.	4 h	50 MBq/nmol (0.75 nM)	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00024	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	0.50%	%	.	.	.	.	Prostate carcinoma	PSMA-negative PC-3 flu cell	.	.	4 h	0.75 nM	ICP-MS or &gamma;-counting assay	"The uptake of [175Lu]Lu-PSMA-617 in PC-3 PIP tumor cells determined by ICP-MS was 57 &plusmn; 5% (after 2 h) and 69 &plusmn; 6% (after 4 h), whereas it was 55 &plusmn; 2% (after 2 h) and 68 &plusmn; 5% (after 4 h) as determined by &gamma;-counting for [<sup>177</sup>Lu]Lu-PSMA-617. For [159Tb]Tb-PSMA-617, the uptake in PC-3 PIP tumor cells determined by ICP-MS was 51 &plusmn; 4% (after 2 h) and 60 &plusmn; 5% (after 4 h), whereas for [161Tb]Tb-PSMA-617, it was 47 &plusmn; 3% (after 2 h) and 54 &plusmn; 6% (after 4 h) as determined by &gamma;-counting."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00025	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	7.8 &plusmn; 0.8 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	2 h	50 MBq/nmol (0.75 nM)	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00025	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	9.7 &plusmn; 0.2 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	4 h	50 MBq/nmol (0.75 nM)	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00025	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	4.8 &plusmn; 0.3 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	2 h	50 MBq/nmol (0.75 nM)	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00025	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	7.0 &plusmn; 0.1 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	4 h	50 MBq/nmol (0.75 nM)	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00025	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell blocking rate	0.10%	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	2 h	50 MBq/nmol (0.75 nM)	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00025	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell blocking rate	0.10%	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	4 h	50 MBq/nmol (0.75 nM)	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00024	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	12 &plusmn; 1 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	2 h	0.75 nM	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00024	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	13 &plusmn; 1 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	4 h	0.75 nM	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00024	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	7.4 &plusmn; 0.4 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	2 h	0.75 nM	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00024	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell internalization rate	9.9 &plusmn; 0.2 %	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	4 h	0.75 nM	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00024	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell blocking rate	0.50%	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	2 h	0.75 nM	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00249	PDC_00024	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell blocking rate	0.50%	%	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	4 h	0.75 nM	ICP-MS or &gamma;-counting assay	"In LNCaP cells, the uptake of [175Lu]Lu-PSMA-617 determined by ICP-MS was 13 &plusmn; 2% (after 2 h) and 18 &plusmn; 2% (after 4 h). &gamma;-Counting revealed the uptake of [<sup>177</sup>Lu]Lu-PSMA-617 in LNCaP cells of 11 &plusmn; 1% (after 2 h) and 14 &plusmn; 1% (after 4 h). For [159Tb]Tb-PSMA-617, analysis by ICP-MS revealed the uptake in LNCaP cells of 12 &plusmn; 1% (after 2 h) and 13 &plusmn; 1% (after 4 h). For the radioligand [161Tb]Tb-PSMA-617, the uptake in LNCaP cells determined by &gamma;-counting was 7.8 &plusmn; 0.8% (after 2 h) and 9.7 &plusmn; 0.2% (after 4 h)."	"This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a proof-of-concept study, the prostate-specific membrane antigen (PSMA)-targeting [175Lu]Lu-PSMA-617 and [159Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [<sup>177</sup>Lu]Lu-PSMA-617 (PLUVICTO, Novartis) and [161Tb]Tb-PSMA-617. ICP-MS and conventional &gamma;-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [175Lu]Lu-/[<sup>177</sup>Lu]Lu-PSMA-617 (41 &plusmn; 6% ID/g and 44 &plusmn; 12% IA/g, respectively) and [159Tb]Tb-/[161Tb]Tb-PSMA-617 (44 &plusmn; 5% ID/g and 44 &plusmn; 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 &plusmn; 2% ID/g vs 10 &plusmn; 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art &gamma;-counting methodology to detect radioactive ligands."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	83%	%	.	.	.	"Patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (1 PCC, 11PGL)."	.	.	.	.	.	.	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	76%	%	.	.	.	"Patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (1 PCC, 11PGL)."	.	.	.	.	.	.	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	16.67%	%	.	.	.	"12 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (1 PCC, 11PGL)."	.	.	.	.	.	7.4 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	20%	%	.	.	.	"5 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (5 PGL, )."	.	.	.	.	3 cycles	6.6-7.6 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	80%	%	.	.	.	"5 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (1PCC, 4PGL)."	.	.	.	.	.	7.4 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	33.33%	%	.	.	.	12 patients with pheocromocytomas and paragangliomas.	.	.	.	.	At least 3 cycles	3.7-8.1 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	100%	%	.	.	.	"5 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (2 PCC, 3PGL)."	.	.	.	.	.	7.4 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	23.33%	%	.	.	.	"30 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (3 PCC, 27PGL)."	.	.	.	.	73% of patients received 4 cycles	7.4 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	9.09%	%	.	.	.	"22 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (9 PCC , 13PGL)."	.	.	.	.	4.9 cycles	7.4 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	6.67%	%	.	.	.	"15 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (5 PCC , 10PGL)."	.	.	.	.	4.13 cycles	.	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	8.82%	%	.	.	.	34 patients with pheocromocytomas and paragangliomas.	.	.	.	.	5 cycles	3.7-5.5 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	22.22%	%	.	.	.	"9 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (3 PCC , 6PGL)."	.	.	.	.	3.11 cycles	8.01 (7.4-8.4) GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	17.95%	%	.	.	.	"39 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (11 PCC, 28PGL)."	.	.	.	.	2 cycles (range: 1-10)	3.7 GBq/mq per cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	7.69%	%	.	.	.	"13 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (4 PCC , 9PGL)."	.	.	.	.	61% of patients received 2 cycles	3.4 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	8.33%	%	.	.	.	12 patients with pheocromocytomas and paragangliomas.	.	.	.	.	5 cycles	1.1-1.85 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	50%	%	.	.	.	"12 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (1 PCC, 11PGL)."	.	.	.	.	.	7.4 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	60%	%	.	.	.	"5 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (5 PGL, )."	.	.	.	.	3 cycles	6.6-7.6 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	16.67%	%	.	.	.	12 patients with pheocromocytomas and paragangliomas.	.	.	.	.	At least 3 cycles	3.7-8.1 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	66.67%	%	.	.	.	"30 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (3 PCC, 27PGL)."	.	.	.	.	73% of patients received 4 cycles	7.4 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	90.91%	%	.	.	.	"22 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (9 PCC , 13PGL)."	.	.	.	.	4.9 cycles	7.4 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	73.33%	%	.	.	.	"15 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (5 PCC , 10PGL)."	.	.	.	.	4.13 cycles	.	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	73.53%	%	.	.	.	34 patients with pheocromocytomas and paragangliomas.	.	.	.	.	5 cycles	3.7-5.5 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	66.67%	%	.	.	.	"9 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (3 PCC , 6PGL)."	.	.	.	.	3.11 cycles	8.01 (7.4-8.4) GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	69.23%	%	.	.	.	"13 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (4 PCC , 9PGL)."	.	.	.	.	61% of patients received 2 cycles	3.4 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	66.67%	%	.	.	.	12 patients with pheocromocytomas and paragangliomas.	.	.	.	.	5 cycles	1.1-1.85 GBq/cycle	.	"There was no statistically significant heterogeneity among the <sup>177</sup>Lu- and 90Y- PRRTs studies (I2 value = 0%, p = 0.68 and I2 value = 0%, p = 0.91, respectively). The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for <sup>177</sup>Lu- and 90Y-PRRT treatments, respectively. The pooled DCR for PRRT agents was 0.81 (95% CI: 0.74-0.87). Although the present study is the largest description of DCR in PRRT therapy of PCCs and PGLs, given the small sample size, no formal attempts were made to compare efficacy between <sup>177</sup>Lu- and 90Y-PRRT treatments. In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia and anemia	16.67%	%	.	.	.	"12 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (1 PCC, 11PGL)."	.	.	.	.	.	7.4 GBq/cycle	.	"In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Anemia	6.67%	%	.	.	.	"30 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (3 PCC, 27PGL)."	.	.	.	.	73% of patients received 4 cycles	7.4 GBq/cycle	.	"In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	16.67%	%	.	.	.	"30 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (3 PCC, 27PGL)."	.	.	.	.	73% of patients received 4 cycles	7.4 GBq/cycle	.	"In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Leukopenia	10%	%	.	.	.	"30 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (3 PCC, 27PGL)."	.	.	.	.	73% of patients received 4 cycles	7.4 GBq/cycle	.	"In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00252	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Anemia	15.38%	%	.	.	.	"13 patients with pheocromocytomas (PCCs) and paragangliomas (PGLs) (4 PCC , 9PGL)."	.	.	.	.	61% of patients received 2 cycles	3.4 GBq/cycle	.	"In detail, we report pooled data on 149 <sup>177</sup>Lu- and 64 90Y-treated patients (total: 213 patients). Most studies were retrospective. The largest one included 46 patients (34 treated with <sup>177</sup>Lu-, 12 with 90Y- PRRTs). Median ages ranged from 32.5 to 60.4 years. The female gender was slightly predominant (83 women, 74 men, gender not specified in 3 studies). When reported, mutations of SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) were the most frequent genetic alterations. According to the predominant retrospective and real practice nature of the selected studies, sites of metastases and previous treatments were heterogeneous, with bone the metastatic site most often involved, and surgery the most frequent previous therapy. Paramount descriptive information on PRRT doses per cycle, number of cycles, response criteria, best responses to treatments, and frequency of G3/G4 hematologic toxicities is reported in Table 2. The lowest applied dose was 3.4 GBq per cycle; the number of administered cycles was heterogeneous (at least 3 cycles in 7 studies). The most used response criteria were the RECIST 1.1. Only one study evaluated the response with SWOG criteria, which are more conservative with regard to the definition of PR (50% or greater reduction in the sum of the product of the perpendicular diameters of target lesions). The majority of the patients experienced PR or SD. Hematologic toxicity was manageable. Funnel plot of selected studies did not show publication bias. The MINORS and Newcastle-Ottawa Scale scoring for the selected articles are reported in Table 3."	"We showed that PRRT based on <sup>177</sup>Lu-DOTATATE and 90-YDOTATOC without radiosensitizers are efficacious therapeutic options (DCR of 83% and 76%, respectively) and can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy."
REF00256	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	17.7 months	months	.	.	.	52 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6-10 weeks for 6 cycles	7.3 GBq (5.9-7.4 GBq)	18F-Fluorodeoxyglucose (FDG) and 68Ga-PSMA (PSMA) Positron Emission Tomography/Computer Tomography (PET/CT) scans assay	"Median OS and PSA-PFS were 17.7 (95% confidence interval [CI]: 15.2-20.2) and 6.6 months (95% CI: 4.5-8.8), respectively. Primary resistance to PSMA-RLT (hazard ratio [HR]: 12.57, 95% CI: 2.4-65.2, p: 0.003), <30% PSA response rate after first cycle of PSMA-RLT (HR: 1.016, 95% CI: 1.006-1.03, p: 0.003), FDG > PSMA disease (HR: 4.9, 95% CI: 1.19-20.62, p: 0.03), PSA doubling time (PSA DT) of &le;2.4 months (HR: 15.7, 95% CI: 3.7-66.4, p: <0.0001), and low hemoglobin levels (HR: 0.59, 95% CI: 0.41-0.83, p: 0.003) were correlated with poor OS in the multivariate analysis. Bone scintigraphy > PSMA disease (HR: 5.6; 95% CI: 1.8-17, p: 0.002) and high C-reactive protein (HR: 1.4, 95% CI: 1.1-1.7, p: 0.001) were significant predictive biomarkers for PFS in the multivariate analysis."	"PSA response patterns, PSA decline rate after the first RLT and pretherapy PSA doubling time are the most important predictors of OS in patients receiving Lu-177 PSMA RLT. FDG PET/CT can be utilized as additional decision-making for PSMA-RLT eligibility since high tumor heterogeneity and the presence of FDG > PSMA disease is associated with poor OS."
REF00256	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	6.6 months	months	.	.	.	52 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 6-10 weeks for 6 cycles	7.3 GBq (5.9-7.4 GBq)	18F-Fluorodeoxyglucose (FDG) and 68Ga-PSMA (PSMA) Positron Emission Tomography/Computer Tomography (PET/CT) scans assay	"Median OS and PSA-PFS were 17.7 (95% confidence interval [CI]: 15.2-20.2) and 6.6 months (95% CI: 4.5-8.8), respectively. Primary resistance to PSMA-RLT (hazard ratio [HR]: 12.57, 95% CI: 2.4-65.2, p: 0.003), <30% PSA response rate after first cycle of PSMA-RLT (HR: 1.016, 95% CI: 1.006-1.03, p: 0.003), FDG > PSMA disease (HR: 4.9, 95% CI: 1.19-20.62, p: 0.03), PSA doubling time (PSA DT) of &le;2.4 months (HR: 15.7, 95% CI: 3.7-66.4, p: <0.0001), and low hemoglobin levels (HR: 0.59, 95% CI: 0.41-0.83, p: 0.003) were correlated with poor OS in the multivariate analysis. Bone scintigraphy > PSMA disease (HR: 5.6; 95% CI: 1.8-17, p: 0.002) and high C-reactive protein (HR: 1.4, 95% CI: 1.1-1.7, p: 0.001) were significant predictive biomarkers for PFS in the multivariate analysis."	"PSA response patterns, PSA decline rate after the first RLT and pretherapy PSA doubling time are the most important predictors of OS in patients receiving Lu-177 PSMA RLT. FDG PET/CT can be utilized as additional decision-making for PSMA-RLT eligibility since high tumor heterogeneity and the presence of FDG > PSMA disease is associated with poor OS."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	56%	%	.	.	.	9 patients with bronchial carcinoids.	.	.	.	.	4 cycles	.	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	33%	%	.	.	.	48 patients with bronchial carcinoids.	.	.	.	.	Median 4 cycles	.	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	39%	%	.	.	.	443 patients with bronchial carcinoids.	.	.	.	.	.	Cumulative dose: 27.8-29.6 GBq	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	29.20%	%	.	.	.	114 patients with bronchial carcinoids.	.	.	.	.	4-6 cycles	.	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Phaeochromocytoma	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	18%	%	.	.	.	12 patients with pheocromocytomas and paragangliomas.	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	18%	%	.	.	.	12 patients with pheocromocytomas and paragangliomas.	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Phaeochromocytoma	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	36%	%	.	.	.	20 patients with phaeochromocytoma and paraganglioma.	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	36%	%	.	.	.	20 patients with phaeochromocytoma and paraganglioma.	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	40%	%	.	.	.	15 patients with meningiomas.	.	.	.	.	4 cycles	.	.	"A few studies evaluated the efficacy of RLT in meningiomas, administrating 2-5 cycles of [90Y]Y-DOTATATE/-DOTATOC or [<sup>177</sup>Lu]Lu-DOTATATE/-DOTATOC. In a meta-analysis performed by Mirian et al., RLToffered as mono-therapy or in combination with other oncological treatmentsallowed a comprehensive DCR of 63% in refractory meningiomas. The 6-month PFS rates were 94%, 48%, and 0% for patients with WHO grade I, II, and III meningiomas, respectively, whereas the corresponding 1-year OS rates were 88%, 71%, and 52%, respectively. In a study by Seystahl et al. RLT, offered mainly with [<sup>177</sup>Lu]Lu-DOTATATE (85% of patients), obtained 6-month PFS rates of 100%, 57%, and 0% for grade I, II, and III refractory meningiomas, respectively. In a recent study on a small group of selected patients affected by WHO grade II refractory meningiomas, 6-month PFS was 85.7% and 1-year PFS was 66.7%. The treatment was safe and well tolerated."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	35%	%	.	.	.	82 patients with CUP-neuroendocrine tumour.	.	.	.	.	4 cycles	.	.	"Unfortunately, the literature lacks specific trials assessing RLT efficacy and safety on CUP-NETs, and the only available literature evidence is provided by mixed trials also including a few patients with SSTR-positive CUP-NETs. In a large cohort of patients treated with [<sup>177</sup>Lu]Lu-DOTATATE, Brabander et al.reported of 82 CUP-NET patients. Overall, DCR was reached in 78% of patients and median PFS and OS were 29 and 53 months, respectively. These results show that RLT may be effective in CUP-NETs patients, with a response rate intermediate between that obtained in GEP-NETswho showed longer median OS (60 vs. 53 months, respectively)and BCswho showed shorter median PFS (20 vs. 29 months, respectively). These results are consistent with those reported by Demirci et al. who treated 19 CUP-NETs, with an overall DCR of 84.2% and mean PFS and OS of 40 and 48 months, respectively. Once again, RLT outcomes in CUP-NETs were intermediate between those in GEP-NETs and BCs. In a large mixed cohort, Baum et al. treated 151 CUP-NETs (mostly with [<sup>177</sup>Lu]Lu-DOTATATE, although a small percentage of patients was treated with [90Y]Y-DOTATATE/DOTATOC in the study), obtaining median PFS and OS of 13 and 46 months, respectively. CUP-NETStogether with BCswere associated with a significantly shorter PFS at multivariate analysis if compared to pancreatic NETs despite showing a longer OS (50 vs. 43 months, respectively). Future prospective trials assessing efficacy and safety of RLT in CUP-NETs are desirable."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	36.80%	%	.	.	.	19 patients with CUP-neuroendocrine tumor.	.	.	.	.	Median 6 cycles	.	.	"Unfortunately, the literature lacks specific trials assessing RLT efficacy and safety on CUP-NETs, and the only available literature evidence is provided by mixed trials also including a few patients with SSTR-positive CUP-NETs. In a large cohort of patients treated with [<sup>177</sup>Lu]Lu-DOTATATE, Brabander et al.reported of 82 CUP-NET patients. Overall, DCR was reached in 78% of patients and median PFS and OS were 29 and 53 months, respectively. These results show that RLT may be effective in CUP-NETs patients, with a response rate intermediate between that obtained in GEP-NETswho showed longer median OS (60 vs. 53 months, respectively)and BCswho showed shorter median PFS (20 vs. 29 months, respectively). These results are consistent with those reported by Demirci et al. who treated 19 CUP-NETs, with an overall DCR of 84.2% and mean PFS and OS of 40 and 48 months, respectively. Once again, RLT outcomes in CUP-NETs were intermediate between those in GEP-NETs and BCs. In a large mixed cohort, Baum et al. treated 151 CUP-NETs (mostly with [<sup>177</sup>Lu]Lu-DOTATATE, although a small percentage of patients was treated with [90Y]Y-DOTATATE/DOTATOC in the study), obtaining median PFS and OS of 13 and 46 months, respectively. CUP-NETStogether with BCswere associated with a significantly shorter PFS at multivariate analysis if compared to pancreatic NETs despite showing a longer OS (50 vs. 43 months, respectively). Future prospective trials assessing efficacy and safety of RLT in CUP-NETs are desirable."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	80%	%	.	.	.	34 patients with bronchial carcinoids.	.	.	.	.	4-5 cycles	.	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	89%	%	.	.	.	9 patients with bronchial carcinoids.	.	.	.	.	4 cycles	.	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	83%	%	.	.	.	48 patients with bronchial carcinoids.	.	.	.	.	Median 4 cycles	.	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	60%	%	.	.	.	443 patients with bronchial carcinoids.	.	.	.	.	.	Cumulative dose: 27.8-29.6 GBq	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	75%	%	.	.	.	114 patients with bronchial carcinoids.	.	.	.	.	4-6 cycles	.	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Phaeochromocytoma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	73%	%	.	.	.	12 patients with pheocromocytomas and paragangliomas.	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	73%	%	.	.	.	12 patients with pheocromocytomas and paragangliomas.	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Phaeochromocytoma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	86%	%	.	.	.	20 patients with phaeochromocytoma and paraganglioma.	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	86%	%	.	.	.	20 patients with phaeochromocytoma and paraganglioma.	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Phaeochromocytoma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	80.40%	%	.	.	.	46 patients with Pheochromocytomas (PPGL) and paragangliomas (PHEO).	.	.	.	.	4-5 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	80.40%	%	.	.	.	46 patients with Pheochromocytomas (PPGL) and paragangliomas (PHEO).	.	.	.	.	4-5 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Phaeochromocytoma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	88.80%	%	.	.	.	9 patients with Pheochromocytomas (PPGL) and paragangliomas (PHEO).	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	88.80%	%	.	.	.	9 patients with Pheochromocytomas (PPGL) and paragangliomas (PHEO).	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	50%	%	.	.	.	20 patients with meningiomas.	.	.	.	.	Median 3 cycles	.	.	"A few studies evaluated the efficacy of RLT in meningiomas, administrating 2-5 cycles of [90Y]Y-DOTATATE/-DOTATOC or [<sup>177</sup>Lu]Lu-DOTATATE/-DOTATOC. In a meta-analysis performed by Mirian et al., RLToffered as mono-therapy or in combination with other oncological treatmentsallowed a comprehensive DCR of 63% in refractory meningiomas. The 6-month PFS rates were 94%, 48%, and 0% for patients with WHO grade I, II, and III meningiomas, respectively, whereas the corresponding 1-year OS rates were 88%, 71%, and 52%, respectively. In a study by Seystahl et al. RLT, offered mainly with [<sup>177</sup>Lu]Lu-DOTATATE (85% of patients), obtained 6-month PFS rates of 100%, 57%, and 0% for grade I, II, and III refractory meningiomas, respectively. In a recent study on a small group of selected patients affected by WHO grade II refractory meningiomas, 6-month PFS was 85.7% and 1-year PFS was 66.7%. The treatment was safe and well tolerated."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	50%	%	.	.	.	20 patients with meningiomas.	.	.	.	.	Median 3 cycles	.	.	"A few studies evaluated the efficacy of RLT in meningiomas, administrating 2-5 cycles of [90Y]Y-DOTATATE/-DOTATOC or [<sup>177</sup>Lu]Lu-DOTATATE/-DOTATOC. In a meta-analysis performed by Mirian et al., RLToffered as mono-therapy or in combination with other oncological treatmentsallowed a comprehensive DCR of 63% in refractory meningiomas. The 6-month PFS rates were 94%, 48%, and 0% for patients with WHO grade I, II, and III meningiomas, respectively, whereas the corresponding 1-year OS rates were 88%, 71%, and 52%, respectively. In a study by Seystahl et al. RLT, offered mainly with [<sup>177</sup>Lu]Lu-DOTATATE (85% of patients), obtained 6-month PFS rates of 100%, 57%, and 0% for grade I, II, and III refractory meningiomas, respectively. In a recent study on a small group of selected patients affected by WHO grade II refractory meningiomas, 6-month PFS was 85.7% and 1-year PFS was 66.7%. The treatment was safe and well tolerated."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	40%	%	.	.	.	15 patients with meningiomas.	.	.	.	.	4 cycles	.	.	"A few studies evaluated the efficacy of RLT in meningiomas, administrating 2-5 cycles of [90Y]Y-DOTATATE/-DOTATOC or [<sup>177</sup>Lu]Lu-DOTATATE/-DOTATOC. In a meta-analysis performed by Mirian et al., RLToffered as mono-therapy or in combination with other oncological treatmentsallowed a comprehensive DCR of 63% in refractory meningiomas. The 6-month PFS rates were 94%, 48%, and 0% for patients with WHO grade I, II, and III meningiomas, respectively, whereas the corresponding 1-year OS rates were 88%, 71%, and 52%, respectively. In a study by Seystahl et al. RLT, offered mainly with [<sup>177</sup>Lu]Lu-DOTATATE (85% of patients), obtained 6-month PFS rates of 100%, 57%, and 0% for grade I, II, and III refractory meningiomas, respectively. In a recent study on a small group of selected patients affected by WHO grade II refractory meningiomas, 6-month PFS was 85.7% and 1-year PFS was 66.7%. The treatment was safe and well tolerated."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	78%	%	.	.	.	82 patients with CUP-neuroendocrine tumour.	.	.	.	.	4 cycles	.	.	"Unfortunately, the literature lacks specific trials assessing RLT efficacy and safety on CUP-NETs, and the only available literature evidence is provided by mixed trials also including a few patients with SSTR-positive CUP-NETs. In a large cohort of patients treated with [<sup>177</sup>Lu]Lu-DOTATATE, Brabander et al.reported of 82 CUP-NET patients. Overall, DCR was reached in 78% of patients and median PFS and OS were 29 and 53 months, respectively. These results show that RLT may be effective in CUP-NETs patients, with a response rate intermediate between that obtained in GEP-NETswho showed longer median OS (60 vs. 53 months, respectively)and BCswho showed shorter median PFS (20 vs. 29 months, respectively). These results are consistent with those reported by Demirci et al. who treated 19 CUP-NETs, with an overall DCR of 84.2% and mean PFS and OS of 40 and 48 months, respectively. Once again, RLT outcomes in CUP-NETs were intermediate between those in GEP-NETs and BCs. In a large mixed cohort, Baum et al. treated 151 CUP-NETs (mostly with [<sup>177</sup>Lu]Lu-DOTATATE, although a small percentage of patients was treated with [90Y]Y-DOTATATE/DOTATOC in the study), obtaining median PFS and OS of 13 and 46 months, respectively. CUP-NETStogether with BCswere associated with a significantly shorter PFS at multivariate analysis if compared to pancreatic NETs despite showing a longer OS (50 vs. 43 months, respectively). Future prospective trials assessing efficacy and safety of RLT in CUP-NETs are desirable."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	84.20%	%	.	.	.	19 patients with CUP-neuroendocrine tumor.	.	.	.	.	Median 6 cycles	.	.	"Unfortunately, the literature lacks specific trials assessing RLT efficacy and safety on CUP-NETs, and the only available literature evidence is provided by mixed trials also including a few patients with SSTR-positive CUP-NETs. In a large cohort of patients treated with [<sup>177</sup>Lu]Lu-DOTATATE, Brabander et al.reported of 82 CUP-NET patients. Overall, DCR was reached in 78% of patients and median PFS and OS were 29 and 53 months, respectively. These results show that RLT may be effective in CUP-NETs patients, with a response rate intermediate between that obtained in GEP-NETswho showed longer median OS (60 vs. 53 months, respectively)and BCswho showed shorter median PFS (20 vs. 29 months, respectively). These results are consistent with those reported by Demirci et al. who treated 19 CUP-NETs, with an overall DCR of 84.2% and mean PFS and OS of 40 and 48 months, respectively. Once again, RLT outcomes in CUP-NETs were intermediate between those in GEP-NETs and BCs. In a large mixed cohort, Baum et al. treated 151 CUP-NETs (mostly with [<sup>177</sup>Lu]Lu-DOTATATE, although a small percentage of patients was treated with [90Y]Y-DOTATATE/DOTATOC in the study), obtaining median PFS and OS of 13 and 46 months, respectively. CUP-NETStogether with BCswere associated with a significantly shorter PFS at multivariate analysis if compared to pancreatic NETs despite showing a longer OS (50 vs. 43 months, respectively). Future prospective trials assessing efficacy and safety of RLT in CUP-NETs are desirable."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Typical bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	20.1 months	months	.	.	.	34 patients with bronchial carcinoids.	.	.	.	.	4-5 cycles	.	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Atypical bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	15.7 months	months	.	.	.	34 patients with bronchial carcinoids.	.	.	.	.	4-5 cycles	.	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	29 months	months	.	.	.	443 patients with bronchial carcinoids.	.	.	.	.	.	Cumulative dose: 27.8-29.6 GBq	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	28 months	months	.	.	.	114 patients with bronchial carcinoids.	.	.	.	.	4-6 cycles	.	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Phaeochromocytoma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	39 months	months	.	.	.	20 patients with phaeochromocytoma and paraganglioma.	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	39 months	months	.	.	.	20 patients with phaeochromocytoma and paraganglioma.	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Phaeochromocytoma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	29 months	months	.	.	.	9 patients with Pheochromocytomas (PPGL) and paragangliomas (PHEO).	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	29 months	months	.	.	.	9 patients with Pheochromocytomas (PPGL) and paragangliomas (PHEO).	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	6 months	months	.	.	.	8 patients with WHO grade II meningiomas.	.	.	.	.	4 cycles	.	.	"A few studies evaluated the efficacy of RLT in meningiomas, administrating 2-5 cycles of [90Y]Y-DOTATATE/-DOTATOC or [<sup>177</sup>Lu]Lu-DOTATATE/-DOTATOC. In a meta-analysis performed by Mirian et al., RLToffered as mono-therapy or in combination with other oncological treatmentsallowed a comprehensive DCR of 63% in refractory meningiomas. The 6-month PFS rates were 94%, 48%, and 0% for patients with WHO grade I, II, and III meningiomas, respectively, whereas the corresponding 1-year OS rates were 88%, 71%, and 52%, respectively. In a study by Seystahl et al. RLT, offered mainly with [<sup>177</sup>Lu]Lu-DOTATATE (85% of patients), obtained 6-month PFS rates of 100%, 57%, and 0% for grade I, II, and III refractory meningiomas, respectively. In a recent study on a small group of selected patients affected by WHO grade II refractory meningiomas, 6-month PFS was 85.7% and 1-year PFS was 66.7%. The treatment was safe and well tolerated."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	32.2 months	months	.	.	.	Patients with WHO grade I meningiomas.	.	.	.	.	Median 3 cycles	.	.	"A few studies evaluated the efficacy of RLT in meningiomas, administrating 2-5 cycles of [90Y]Y-DOTATATE/-DOTATOC or [<sup>177</sup>Lu]Lu-DOTATATE/-DOTATOC. In a meta-analysis performed by Mirian et al., RLToffered as mono-therapy or in combination with other oncological treatmentsallowed a comprehensive DCR of 63% in refractory meningiomas. The 6-month PFS rates were 94%, 48%, and 0% for patients with WHO grade I, II, and III meningiomas, respectively, whereas the corresponding 1-year OS rates were 88%, 71%, and 52%, respectively. In a study by Seystahl et al. RLT, offered mainly with [<sup>177</sup>Lu]Lu-DOTATATE (85% of patients), obtained 6-month PFS rates of 100%, 57%, and 0% for grade I, II, and III refractory meningiomas, respectively. In a recent study on a small group of selected patients affected by WHO grade II refractory meningiomas, 6-month PFS was 85.7% and 1-year PFS was 66.7%. The treatment was safe and well tolerated."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	7.6 months	months	.	.	.	Patients with WHO grade II meningiomas.	.	.	.	.	Median 3 cycles	.	.	"A few studies evaluated the efficacy of RLT in meningiomas, administrating 2-5 cycles of [90Y]Y-DOTATATE/-DOTATOC or [<sup>177</sup>Lu]Lu-DOTATATE/-DOTATOC. In a meta-analysis performed by Mirian et al., RLToffered as mono-therapy or in combination with other oncological treatmentsallowed a comprehensive DCR of 63% in refractory meningiomas. The 6-month PFS rates were 94%, 48%, and 0% for patients with WHO grade I, II, and III meningiomas, respectively, whereas the corresponding 1-year OS rates were 88%, 71%, and 52%, respectively. In a study by Seystahl et al. RLT, offered mainly with [<sup>177</sup>Lu]Lu-DOTATATE (85% of patients), obtained 6-month PFS rates of 100%, 57%, and 0% for grade I, II, and III refractory meningiomas, respectively. In a recent study on a small group of selected patients affected by WHO grade II refractory meningiomas, 6-month PFS was 85.7% and 1-year PFS was 66.7%. The treatment was safe and well tolerated."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	2.1 months	months	.	.	.	Patients with WHO grade III meningiomas.	.	.	.	.	Median 3 cycles	.	.	"A few studies evaluated the efficacy of RLT in meningiomas, administrating 2-5 cycles of [90Y]Y-DOTATATE/-DOTATOC or [<sup>177</sup>Lu]Lu-DOTATATE/-DOTATOC. In a meta-analysis performed by Mirian et al., RLToffered as mono-therapy or in combination with other oncological treatmentsallowed a comprehensive DCR of 63% in refractory meningiomas. The 6-month PFS rates were 94%, 48%, and 0% for patients with WHO grade I, II, and III meningiomas, respectively, whereas the corresponding 1-year OS rates were 88%, 71%, and 52%, respectively. In a study by Seystahl et al. RLT, offered mainly with [<sup>177</sup>Lu]Lu-DOTATATE (85% of patients), obtained 6-month PFS rates of 100%, 57%, and 0% for grade I, II, and III refractory meningiomas, respectively. In a recent study on a small group of selected patients affected by WHO grade II refractory meningiomas, 6-month PFS was 85.7% and 1-year PFS was 66.7%. The treatment was safe and well tolerated."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	7.8 months	months	.	.	.	15 patients with meningiomas.	.	.	.	.	4 cycles	.	.	"A few studies evaluated the efficacy of RLT in meningiomas, administrating 2-5 cycles of [90Y]Y-DOTATATE/-DOTATOC or [<sup>177</sup>Lu]Lu-DOTATATE/-DOTATOC. In a meta-analysis performed by Mirian et al., RLToffered as mono-therapy or in combination with other oncological treatmentsallowed a comprehensive DCR of 63% in refractory meningiomas. The 6-month PFS rates were 94%, 48%, and 0% for patients with WHO grade I, II, and III meningiomas, respectively, whereas the corresponding 1-year OS rates were 88%, 71%, and 52%, respectively. In a study by Seystahl et al. RLT, offered mainly with [<sup>177</sup>Lu]Lu-DOTATATE (85% of patients), obtained 6-month PFS rates of 100%, 57%, and 0% for grade I, II, and III refractory meningiomas, respectively. In a recent study on a small group of selected patients affected by WHO grade II refractory meningiomas, 6-month PFS was 85.7% and 1-year PFS was 66.7%. The treatment was safe and well tolerated."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	29 months	months	.	.	.	82 patients with CUP-neuroendocrine tumour.	.	.	.	.	4 cycles	.	.	"Unfortunately, the literature lacks specific trials assessing RLT efficacy and safety on CUP-NETs, and the only available literature evidence is provided by mixed trials also including a few patients with SSTR-positive CUP-NETs. In a large cohort of patients treated with [<sup>177</sup>Lu]Lu-DOTATATE, Brabander et al.reported of 82 CUP-NET patients. Overall, DCR was reached in 78% of patients and median PFS and OS were 29 and 53 months, respectively. These results show that RLT may be effective in CUP-NETs patients, with a response rate intermediate between that obtained in GEP-NETswho showed longer median OS (60 vs. 53 months, respectively)and BCswho showed shorter median PFS (20 vs. 29 months, respectively). These results are consistent with those reported by Demirci et al. who treated 19 CUP-NETs, with an overall DCR of 84.2% and mean PFS and OS of 40 and 48 months, respectively. Once again, RLT outcomes in CUP-NETs were intermediate between those in GEP-NETs and BCs. In a large mixed cohort, Baum et al. treated 151 CUP-NETs (mostly with [<sup>177</sup>Lu]Lu-DOTATATE, although a small percentage of patients was treated with [90Y]Y-DOTATATE/DOTATOC in the study), obtaining median PFS and OS of 13 and 46 months, respectively. CUP-NETStogether with BCswere associated with a significantly shorter PFS at multivariate analysis if compared to pancreatic NETs despite showing a longer OS (50 vs. 43 months, respectively). Future prospective trials assessing efficacy and safety of RLT in CUP-NETs are desirable."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	40.9 months	months	.	.	.	19 patients with CUP-neuroendocrine tumor.	.	.	.	.	Median 6 cycles	.	.	"Unfortunately, the literature lacks specific trials assessing RLT efficacy and safety on CUP-NETs, and the only available literature evidence is provided by mixed trials also including a few patients with SSTR-positive CUP-NETs. In a large cohort of patients treated with [<sup>177</sup>Lu]Lu-DOTATATE, Brabander et al.reported of 82 CUP-NET patients. Overall, DCR was reached in 78% of patients and median PFS and OS were 29 and 53 months, respectively. These results show that RLT may be effective in CUP-NETs patients, with a response rate intermediate between that obtained in GEP-NETswho showed longer median OS (60 vs. 53 months, respectively)and BCswho showed shorter median PFS (20 vs. 29 months, respectively). These results are consistent with those reported by Demirci et al. who treated 19 CUP-NETs, with an overall DCR of 84.2% and mean PFS and OS of 40 and 48 months, respectively. Once again, RLT outcomes in CUP-NETs were intermediate between those in GEP-NETs and BCs. In a large mixed cohort, Baum et al. treated 151 CUP-NETs (mostly with [<sup>177</sup>Lu]Lu-DOTATATE, although a small percentage of patients was treated with [90Y]Y-DOTATATE/DOTATOC in the study), obtaining median PFS and OS of 13 and 46 months, respectively. CUP-NETStogether with BCswere associated with a significantly shorter PFS at multivariate analysis if compared to pancreatic NETs despite showing a longer OS (50 vs. 43 months, respectively). Future prospective trials assessing efficacy and safety of RLT in CUP-NETs are desirable."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	13 months	months	.	.	.	1048 patients with CUP-neuroendocrine tumour.	.	.	.	.	4 cycles	.	.	"Unfortunately, the literature lacks specific trials assessing RLT efficacy and safety on CUP-NETs, and the only available literature evidence is provided by mixed trials also including a few patients with SSTR-positive CUP-NETs. In a large cohort of patients treated with [<sup>177</sup>Lu]Lu-DOTATATE, Brabander et al.reported of 82 CUP-NET patients. Overall, DCR was reached in 78% of patients and median PFS and OS were 29 and 53 months, respectively. These results show that RLT may be effective in CUP-NETs patients, with a response rate intermediate between that obtained in GEP-NETswho showed longer median OS (60 vs. 53 months, respectively)and BCswho showed shorter median PFS (20 vs. 29 months, respectively). These results are consistent with those reported by Demirci et al. who treated 19 CUP-NETs, with an overall DCR of 84.2% and mean PFS and OS of 40 and 48 months, respectively. Once again, RLT outcomes in CUP-NETs were intermediate between those in GEP-NETs and BCs. In a large mixed cohort, Baum et al. treated 151 CUP-NETs (mostly with [<sup>177</sup>Lu]Lu-DOTATATE, although a small percentage of patients was treated with [90Y]Y-DOTATATE/DOTATOC in the study), obtaining median PFS and OS of 13 and 46 months, respectively. CUP-NETStogether with BCswere associated with a significantly shorter PFS at multivariate analysis if compared to pancreatic NETs despite showing a longer OS (50 vs. 43 months, respectively). Future prospective trials assessing efficacy and safety of RLT in CUP-NETs are desirable."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	48.6 months	months	.	.	.	34 patients with bronchial carcinoids.	.	.	.	.	4-5 cycles	.	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	49 months	months	.	.	.	48 patients with bronchial carcinoids.	.	.	.	.	Median 4 cycles	.	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	63 months	months	.	.	.	443 patients with bronchial carcinoids.	.	.	.	.	.	Cumulative dose: 27.8-29.6 GBq	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Bronchial carcinoids	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	58.8 months	months	.	.	.	114 patients with bronchial carcinoids.	.	.	.	.	4-6 cycles	.	.	"Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, cold somatostatin analogues, immunotherapy, everolimus, and others target therapies. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to cold SSAs therapy. Although the experience of [<sup>177</sup>Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [<sup>177</sup>Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [18F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies. Higher activities were administered in a study by van Essen et al., who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [<sup>177</sup>Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. in a study involving 443 patients affected by midgut, bronchial, and CUP-NETs treated with 7.4 GBq of [<sup>177</sup>Lu]Lu-DOTATATE every 8 weeks. The authors found that objective response rate (ORR) for BCs was 30%, and an additional 30% of patients had a stable disease. Nevertheless, median OS for BCs was 52 months versus 71 months for pancreatic-NET. Long term results were analyzed by Mariniello et al. in 114 patients with advanced BCs treated with different RLT protocols. They documented a median PFS and OS of 28.0 and 58.8 months, respectively, while morphological responses were observed in 26.5% of patients. [<sup>177</sup>Lu]Lu-DOTATATE monotherapy protocol resulted in the highest 5-year OS (61.4%), despite tandem protocol ([90Y]Y-DOTATOC + [<sup>177</sup>Lu]Lu-DOTATATE) provided the highest response rates (38.1%). Best outcome was reached in patients who underwent RLT in early stage of disease, suggesting that this treatment should also be considered for newly diagnosed unresectable BCs. Moreover, despite most patients having only mild and transient adverse events, patients with hematologic toxicity showed worse survival outcomes."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Phaeochromocytoma	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	28 months	months	.	.	.	20 patients with phaeochromocytoma and paraganglioma.	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	28 months	months	.	.	.	20 patients with phaeochromocytoma and paraganglioma.	.	.	.	.	4 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Phaeochromocytoma	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	142.6 months	months	.	.	.	46 patients with Pheochromocytomas (PPGL) and paragangliomas (PHEO).	.	.	.	.	4-5 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Paraganglioma	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	142.6 months	months	.	.	.	46 patients with Pheochromocytomas (PPGL) and paragangliomas (PHEO).	.	.	.	.	4-5 cycles	.	.	"As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera and other similar radiocompounds, with promising preliminary results. The first RLT experience in PPGLs was reported by van Essen et al. who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with other reports in the literature. Kong et al. treated 20 PPGLs (8 PHEOs and 12 PGLs) with [117Lu]Lu-DOTATATE, 14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al., who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [<sup>177</sup>Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [90Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATEs higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of <sup>177</sup>Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. treated nine patients with [<sup>177</sup>Lu]Lu-DOTATATE and eight with [131I]MIBG, obtaining a PFS of 29 and 18.5 months and a DCR of 88.8% and 62.5%, respectively, for each therapy. Despite the low number of patients involved, a trend for a longer PFS was found for adrenal primary PPGLs treated with [<sup>177</sup>Lu]Lu-DOTATATE. Nevertheless, the authors suggest performing both [68Ga]Ga-DOTA-SSA PET/CT and [123I]MIBG SPECT/CT in each patient in order to offer a personalized theranostic approach based on the highest uptake intensity in one of the two imaging scans. This is consistent with the results by Jaiswal et al. who found that a baseline SUVmax > 21 at [68Ga]Ga-DOTA-SSA PET/CT is a very strong predictor of response to [<sup>177</sup>Lu]Lu-DOTATATE (p < 0.0001)."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	17.2 months	months	.	.	.	20 patients with WHO grade III meningiomas.	.	.	.	.	Median 3 cycles	.	.	"A few studies evaluated the efficacy of RLT in meningiomas, administrating 2-5 cycles of [90Y]Y-DOTATATE/-DOTATOC or [<sup>177</sup>Lu]Lu-DOTATATE/-DOTATOC. In a meta-analysis performed by Mirian et al., RLToffered as mono-therapy or in combination with other oncological treatmentsallowed a comprehensive DCR of 63% in refractory meningiomas. The 6-month PFS rates were 94%, 48%, and 0% for patients with WHO grade I, II, and III meningiomas, respectively, whereas the corresponding 1-year OS rates were 88%, 71%, and 52%, respectively. In a study by Seystahl et al. RLT, offered mainly with [<sup>177</sup>Lu]Lu-DOTATATE (85% of patients), obtained 6-month PFS rates of 100%, 57%, and 0% for grade I, II, and III refractory meningiomas, respectively. In a recent study on a small group of selected patients affected by WHO grade II refractory meningiomas, 6-month PFS was 85.7% and 1-year PFS was 66.7%. The treatment was safe and well tolerated."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Meningiomas	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	13.6 months	months	.	.	.	15 patients with meningiomas.	.	.	.	.	4 cycles	.	.	"A few studies evaluated the efficacy of RLT in meningiomas, administrating 2-5 cycles of [90Y]Y-DOTATATE/-DOTATOC or [<sup>177</sup>Lu]Lu-DOTATATE/-DOTATOC. In a meta-analysis performed by Mirian et al., RLToffered as mono-therapy or in combination with other oncological treatmentsallowed a comprehensive DCR of 63% in refractory meningiomas. The 6-month PFS rates were 94%, 48%, and 0% for patients with WHO grade I, II, and III meningiomas, respectively, whereas the corresponding 1-year OS rates were 88%, 71%, and 52%, respectively. In a study by Seystahl et al. RLT, offered mainly with [<sup>177</sup>Lu]Lu-DOTATATE (85% of patients), obtained 6-month PFS rates of 100%, 57%, and 0% for grade I, II, and III refractory meningiomas, respectively. In a recent study on a small group of selected patients affected by WHO grade II refractory meningiomas, 6-month PFS was 85.7% and 1-year PFS was 66.7%. The treatment was safe and well tolerated."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	53 months	months	.	.	.	82 patients with CUP-neuroendocrine tumour.	.	.	.	.	4 cycles	.	.	"Unfortunately, the literature lacks specific trials assessing RLT efficacy and safety on CUP-NETs, and the only available literature evidence is provided by mixed trials also including a few patients with SSTR-positive CUP-NETs. In a large cohort of patients treated with [<sup>177</sup>Lu]Lu-DOTATATE, Brabander et al.reported of 82 CUP-NET patients. Overall, DCR was reached in 78% of patients and median PFS and OS were 29 and 53 months, respectively. These results show that RLT may be effective in CUP-NETs patients, with a response rate intermediate between that obtained in GEP-NETswho showed longer median OS (60 vs. 53 months, respectively)and BCswho showed shorter median PFS (20 vs. 29 months, respectively). These results are consistent with those reported by Demirci et al. who treated 19 CUP-NETs, with an overall DCR of 84.2% and mean PFS and OS of 40 and 48 months, respectively. Once again, RLT outcomes in CUP-NETs were intermediate between those in GEP-NETs and BCs. In a large mixed cohort, Baum et al. treated 151 CUP-NETs (mostly with [<sup>177</sup>Lu]Lu-DOTATATE, although a small percentage of patients was treated with [90Y]Y-DOTATATE/DOTATOC in the study), obtaining median PFS and OS of 13 and 46 months, respectively. CUP-NETStogether with BCswere associated with a significantly shorter PFS at multivariate analysis if compared to pancreatic NETs despite showing a longer OS (50 vs. 43 months, respectively). Future prospective trials assessing efficacy and safety of RLT in CUP-NETs are desirable."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	48.3 months	months	.	.	.	19 patients with CUP-neuroendocrine tumor.	.	.	.	.	Median 6 cycles	.	.	"Unfortunately, the literature lacks specific trials assessing RLT efficacy and safety on CUP-NETs, and the only available literature evidence is provided by mixed trials also including a few patients with SSTR-positive CUP-NETs. In a large cohort of patients treated with [<sup>177</sup>Lu]Lu-DOTATATE, Brabander et al.reported of 82 CUP-NET patients. Overall, DCR was reached in 78% of patients and median PFS and OS were 29 and 53 months, respectively. These results show that RLT may be effective in CUP-NETs patients, with a response rate intermediate between that obtained in GEP-NETswho showed longer median OS (60 vs. 53 months, respectively)and BCswho showed shorter median PFS (20 vs. 29 months, respectively). These results are consistent with those reported by Demirci et al. who treated 19 CUP-NETs, with an overall DCR of 84.2% and mean PFS and OS of 40 and 48 months, respectively. Once again, RLT outcomes in CUP-NETs were intermediate between those in GEP-NETs and BCs. In a large mixed cohort, Baum et al. treated 151 CUP-NETs (mostly with [<sup>177</sup>Lu]Lu-DOTATATE, although a small percentage of patients was treated with [90Y]Y-DOTATATE/DOTATOC in the study), obtaining median PFS and OS of 13 and 46 months, respectively. CUP-NETStogether with BCswere associated with a significantly shorter PFS at multivariate analysis if compared to pancreatic NETs despite showing a longer OS (50 vs. 43 months, respectively). Future prospective trials assessing efficacy and safety of RLT in CUP-NETs are desirable."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00260	PDC_00027	Neuroendocrine tumour	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	53 months	months	.	.	.	1048 patients with CUP-neuroendocrine tumour.	.	.	.	.	4 cycles	.	.	"Unfortunately, the literature lacks specific trials assessing RLT efficacy and safety on CUP-NETs, and the only available literature evidence is provided by mixed trials also including a few patients with SSTR-positive CUP-NETs. In a large cohort of patients treated with [<sup>177</sup>Lu]Lu-DOTATATE, Brabander et al.reported of 82 CUP-NET patients. Overall, DCR was reached in 78% of patients and median PFS and OS were 29 and 53 months, respectively. These results show that RLT may be effective in CUP-NETs patients, with a response rate intermediate between that obtained in GEP-NETswho showed longer median OS (60 vs. 53 months, respectively)and BCswho showed shorter median PFS (20 vs. 29 months, respectively). These results are consistent with those reported by Demirci et al. who treated 19 CUP-NETs, with an overall DCR of 84.2% and mean PFS and OS of 40 and 48 months, respectively. Once again, RLT outcomes in CUP-NETs were intermediate between those in GEP-NETs and BCs. In a large mixed cohort, Baum et al. treated 151 CUP-NETs (mostly with [<sup>177</sup>Lu]Lu-DOTATATE, although a small percentage of patients was treated with [90Y]Y-DOTATATE/DOTATOC in the study), obtaining median PFS and OS of 13 and 46 months, respectively. CUP-NETStogether with BCswere associated with a significantly shorter PFS at multivariate analysis if compared to pancreatic NETs despite showing a longer OS (50 vs. 43 months, respectively). Future prospective trials assessing efficacy and safety of RLT in CUP-NETs are desirable."	"Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [<sup>177</sup>Lu][Lu-DOTA,Tyr3]octreotate ([<sup>177</sup>Lu]Lu-DOTATATE). The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [<sup>177</sup>Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone. As a consequence of NETTER-1 results, [<sup>177</sup>Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera). Currently, Lutathera is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera, giving rise to the so-called Lutathera Orphans. Indeed, Lutathera is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. Therefore, paediatric patients cannot be treated with Lutathera."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	64%	%	.	.	.	82 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 dose	.	.	"One study retrospectively analyzed 82 mCRPC patients who received a single dose of Lu-PSMA. Tolerability and response to treatment were assessed using hematologic parameters, renal scintigraphy, clinical data, and prostate-specific antigen (PSA) levels. A PSA decline from baseline was noted in 64% patients with 31% of patients having a greater than 50% decline, while 47% patients had stable disease with a 25-50% decrease in PSA levels. Only 25% of patients showed an increase in PSA levels indicating disease progression, and 7% of patients died due to extensive disease."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	31.00%	%	.	.	.	82 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 dose	.	.	"One study retrospectively analyzed 82 mCRPC patients who received a single dose of Lu-PSMA. Tolerability and response to treatment were assessed using hematologic parameters, renal scintigraphy, clinical data, and prostate-specific antigen (PSA) levels. A PSA decline from baseline was noted in 64% patients with 31% of patients having a greater than 50% decline, while 47% patients had stable disease with a 25-50% decrease in PSA levels. Only 25% of patients showed an increase in PSA levels indicating disease progression, and 7% of patients died due to extensive disease."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	45.00%	%	.	.	.	145 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-4 cycles	.	.	"A 2014-2015 retrospective multi-institutional study looked to evaluate the efficacy and safety of <sup>177</sup>Lu-PSMA-617 in a larger population of patients. 145 patients with a median age of 73 years (range 43-88) with mCRPC were treated with a range of 1-4 cycles of treatment. Median follow-up time was sixteen weeks (range 2-30). The primary endpoint of the study was biochemical response, which was defined as a decline in PSA greater than 50% from baseline and secondary endpoints included toxicity. A total of 248 cycles of treatment were carried out in 145 patients with the overall biochemical response rate of 45% after conclusion of all treatment and 40% of patients becoming responders after only one cycle of treatment."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	40.00%	%	.	.	.	145 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 cycles	.	.	"A 2014-2015 retrospective multi-institutional study looked to evaluate the efficacy and safety of <sup>177</sup>Lu-PSMA-617 in a larger population of patients. 145 patients with a median age of 73 years (range 43-88) with mCRPC were treated with a range of 1-4 cycles of treatment. Median follow-up time was sixteen weeks (range 2-30). The primary endpoint of the study was biochemical response, which was defined as a decline in PSA greater than 50% from baseline and secondary endpoints included toxicity. A total of 248 cycles of treatment were carried out in 145 patients with the overall biochemical response rate of 45% after conclusion of all treatment and 40% of patients becoming responders after only one cycle of treatment."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	52 weeks	weeks	.	.	.	43 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every six to twelve weeks	.	.	"A single center retrospective study reviewed 43 mCRPC patients with a median age of 71 (range 51-88) and <sup>177</sup>Lu-PSMA-617 treatments every six to twelve weeks. A total of 112 cycles of RLT were conducted with a median of three cycles (range 1-6). Endpoints included PSA response, toxicity, median OS, and median PSA PFS. A PSA decline of greater than 90% was seen in 23% of patients, while a decline of greater than 50% was seen in 65% of patients. A median OS was 52 weeks, while a PSA PFS was found to be 20 weeks."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	20 weeks	weeks	.	.	.	43 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every six to twelve weeks	.	.	"A single center retrospective study reviewed 43 mCRPC patients with a median age of 71 (range 51-88) and <sup>177</sup>Lu-PSMA-617 treatments every six to twelve weeks. A total of 112 cycles of RLT were conducted with a median of three cycles (range 1-6). Endpoints included PSA response, toxicity, median OS, and median PSA PFS. A PSA decline of greater than 90% was seen in 23% of patients, while a decline of greater than 50% was seen in 65% of patients. A median OS was 52 weeks, while a PSA PFS was found to be 20 weeks."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>90% PSA decline	23.00%	%	.	.	.	43 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every six to twelve weeks	.	.	"A single center retrospective study reviewed 43 mCRPC patients with a median age of 71 (range 51-88) and <sup>177</sup>Lu-PSMA-617 treatments every six to twelve weeks. A total of 112 cycles of RLT were conducted with a median of three cycles (range 1-6). Endpoints included PSA response, toxicity, median OS, and median PSA PFS. A PSA decline of greater than 90% was seen in 23% of patients, while a decline of greater than 50% was seen in 65% of patients. A median OS was 52 weeks, while a PSA PFS was found to be 20 weeks."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	65.00%	%	.	.	.	43 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every six to twelve weeks	.	.	"A single center retrospective study reviewed 43 mCRPC patients with a median age of 71 (range 51-88) and <sup>177</sup>Lu-PSMA-617 treatments every six to twelve weeks. A total of 112 cycles of RLT were conducted with a median of three cycles (range 1-6). Endpoints included PSA response, toxicity, median OS, and median PSA PFS. A PSA decline of greater than 90% was seen in 23% of patients, while a decline of greater than 50% was seen in 65% of patients. A median OS was 52 weeks, while a PSA PFS was found to be 20 weeks."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	32 weeks	weeks	.	.	.	59 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles	.	.	"Another study retrospectively studied fifty-nine mCRPC patients after receiving at least one antihormonal drug as well as chemotherapy. These patients were treated with a median of three cycles of <sup>177</sup>Lu-PSMA-61. The primary end point was overall survival, and secondary end point was decrease in PSA level. Follow-up data was available for forty-five patients with 91% showing a PSA decline. A decline in PSA levels of greater than or equal to 50% occurred in 53% of the patients. The median overall survival was 32 weeks. An initial alkaline phosphatase (ALP) level less than 220 U/L and a PSA decline after the first cycle were associated with a longer overall survival (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). Toxicity overview showed grade 3 leukopenia and thrombocytopenia in 3% patients and grade 3 anemia in 19%. No grade 3 or 4 nephrotoxicity or grade 4 blood toxicity was observed. This study showed a statistically significant decline in ALP levels after the first cycle of <sup>177</sup>Lu-PSMA-617."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	91%	%	.	.	.	59 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles	.	.	"Another study retrospectively studied fifty-nine mCRPC patients after receiving at least one antihormonal drug as well as chemotherapy. These patients were treated with a median of three cycles of <sup>177</sup>Lu-PSMA-61. The primary end point was overall survival, and secondary end point was decrease in PSA level. Follow-up data was available for forty-five patients with 91% showing a PSA decline. A decline in PSA levels of greater than or equal to 50% occurred in 53% of the patients. The median overall survival was 32 weeks. An initial alkaline phosphatase (ALP) level less than 220 U/L and a PSA decline after the first cycle were associated with a longer overall survival (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). Toxicity overview showed grade 3 leukopenia and thrombocytopenia in 3% patients and grade 3 anemia in 19%. No grade 3 or 4 nephrotoxicity or grade 4 blood toxicity was observed. This study showed a statistically significant decline in ALP levels after the first cycle of <sup>177</sup>Lu-PSMA-617."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	53.00%	%	.	.	.	59 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles	.	.	"Another study retrospectively studied fifty-nine mCRPC patients after receiving at least one antihormonal drug as well as chemotherapy. These patients were treated with a median of three cycles of <sup>177</sup>Lu-PSMA-61. The primary end point was overall survival, and secondary end point was decrease in PSA level. Follow-up data was available for forty-five patients with 91% showing a PSA decline. A decline in PSA levels of greater than or equal to 50% occurred in 53% of the patients. The median overall survival was 32 weeks. An initial alkaline phosphatase (ALP) level less than 220 U/L and a PSA decline after the first cycle were associated with a longer overall survival (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). Toxicity overview showed grade 3 leukopenia and thrombocytopenia in 3% patients and grade 3 anemia in 19%. No grade 3 or 4 nephrotoxicity or grade 4 blood toxicity was observed. This study showed a statistically significant decline in ALP levels after the first cycle of <sup>177</sup>Lu-PSMA-617."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 leukopenia/thrombocytopenia	3%	%	.	.	.	59 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles	.	.	"Another study retrospectively studied fifty-nine mCRPC patients after receiving at least one antihormonal drug as well as chemotherapy. These patients were treated with a median of three cycles of <sup>177</sup>Lu-PSMA-61. The primary end point was overall survival, and secondary end point was decrease in PSA level. Follow-up data was available for forty-five patients with 91% showing a PSA decline. A decline in PSA levels of greater than or equal to 50% occurred in 53% of the patients. The median overall survival was 32 weeks. An initial alkaline phosphatase (ALP) level less than 220 U/L and a PSA decline after the first cycle were associated with a longer overall survival (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). Toxicity overview showed grade 3 leukopenia and thrombocytopenia in 3% patients and grade 3 anemia in 19%. No grade 3 or 4 nephrotoxicity or grade 4 blood toxicity was observed. This study showed a statistically significant decline in ALP levels after the first cycle of <sup>177</sup>Lu-PSMA-617."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 anemia	19%	%	.	.	.	59 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles	.	.	"Another study retrospectively studied fifty-nine mCRPC patients after receiving at least one antihormonal drug as well as chemotherapy. These patients were treated with a median of three cycles of <sup>177</sup>Lu-PSMA-61. The primary end point was overall survival, and secondary end point was decrease in PSA level. Follow-up data was available for forty-five patients with 91% showing a PSA decline. A decline in PSA levels of greater than or equal to 50% occurred in 53% of the patients. The median overall survival was 32 weeks. An initial alkaline phosphatase (ALP) level less than 220 U/L and a PSA decline after the first cycle were associated with a longer overall survival (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). Toxicity overview showed grade 3 leukopenia and thrombocytopenia in 3% patients and grade 3 anemia in 19%. No grade 3 or 4 nephrotoxicity or grade 4 blood toxicity was observed. This study showed a statistically significant decline in ALP levels after the first cycle of <sup>177</sup>Lu-PSMA-617."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	29.4 weeks	weeks	.	.	.	28 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A retrospective analysis studied 28 patients with mCRPC who were treated with <sup>177</sup>Lu-PSMA-617 [Citation47]. The estimated median survival was 29.4 weeks, significantly longer than survival in the supportive care group (HR, 0.44; 95% confidence interval, 0.20-0.95]; P = 0.031). Results of the study noted any PSA decline in 59% of patients after one cycle and 75% of patients after two cycles of treatment, while there was a noted PSA decline of 50% or greater in 32% of patients after one cycle of treatment and in 50% of patients after two cycles of treatment. Although this study found a 50% or greater PSA decline in majority of treated patients, 83% of patients reported a stable or improved quality of life after treatment."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	59%	%	.	.	.	28 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A retrospective analysis studied 28 patients with mCRPC who were treated with <sup>177</sup>Lu-PSMA-617 [Citation47]. The estimated median survival was 29.4 weeks, significantly longer than survival in the supportive care group (HR, 0.44; 95% confidence interval, 0.20-0.95]; P = 0.031). Results of the study noted any PSA decline in 59% of patients after one cycle and 75% of patients after two cycles of treatment, while there was a noted PSA decline of 50% or greater in 32% of patients after one cycle of treatment and in 50% of patients after two cycles of treatment. Although this study found a 50% or greater PSA decline in majority of treated patients, 83% of patients reported a stable or improved quality of life after treatment."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	75%	%	.	.	.	28 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A retrospective analysis studied 28 patients with mCRPC who were treated with <sup>177</sup>Lu-PSMA-617 [Citation47]. The estimated median survival was 29.4 weeks, significantly longer than survival in the supportive care group (HR, 0.44; 95% confidence interval, 0.20-0.95]; P = 0.031). Results of the study noted any PSA decline in 59% of patients after one cycle and 75% of patients after two cycles of treatment, while there was a noted PSA decline of 50% or greater in 32% of patients after one cycle of treatment and in 50% of patients after two cycles of treatment. Although this study found a 50% or greater PSA decline in majority of treated patients, 83% of patients reported a stable or improved quality of life after treatment."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	32.00%	%	.	.	.	28 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A retrospective analysis studied 28 patients with mCRPC who were treated with <sup>177</sup>Lu-PSMA-617 [Citation47]. The estimated median survival was 29.4 weeks, significantly longer than survival in the supportive care group (HR, 0.44; 95% confidence interval, 0.20-0.95]; P = 0.031). Results of the study noted any PSA decline in 59% of patients after one cycle and 75% of patients after two cycles of treatment, while there was a noted PSA decline of 50% or greater in 32% of patients after one cycle of treatment and in 50% of patients after two cycles of treatment. Although this study found a 50% or greater PSA decline in majority of treated patients, 83% of patients reported a stable or improved quality of life after treatment."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	50.00%	%	.	.	.	28 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A retrospective analysis studied 28 patients with mCRPC who were treated with <sup>177</sup>Lu-PSMA-617 [Citation47]. The estimated median survival was 29.4 weeks, significantly longer than survival in the supportive care group (HR, 0.44; 95% confidence interval, 0.20-0.95]; P = 0.031). Results of the study noted any PSA decline in 59% of patients after one cycle and 75% of patients after two cycles of treatment, while there was a noted PSA decline of 50% or greater in 32% of patients after one cycle of treatment and in 50% of patients after two cycles of treatment. Although this study found a 50% or greater PSA decline in majority of treated patients, 83% of patients reported a stable or improved quality of life after treatment."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	70%	%	.	.	.	30 patients with PSMA-positive prostate tumor.	.	.	.	.	.	.	.	"<sup>177</sup>Lu-PSMA-617 was offered to thirty patients with PSMA-positive prostate tumor. Treatment efficacy was retrospectively assessed by PSA levels with 70% of patients demonstrating a decrease in PSA levels. 18 patients were noted to have PSA decline greater than 25%, while 13 patients had a decline greater than 50%. Six of these patients were restaged using PSMA PET/CT (positron emission tomography/computed tomography), and all six patients had a response rate of more than 50% in SUVmax (maximum standardized uptake value) of the tumor."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>25% PSA decline	60.00%	%	.	.	.	30 patients with PSMA-positive prostate tumor.	.	.	.	.	.	.	.	"<sup>177</sup>Lu-PSMA-617 was offered to thirty patients with PSMA-positive prostate tumor. Treatment efficacy was retrospectively assessed by PSA levels with 70% of patients demonstrating a decrease in PSA levels. 18 patients were noted to have PSA decline greater than 25%, while 13 patients had a decline greater than 50%. Six of these patients were restaged using PSMA PET/CT (positron emission tomography/computed tomography), and all six patients had a response rate of more than 50% in SUVmax (maximum standardized uptake value) of the tumor."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	43.33%	%	.	.	.	30 patients with PSMA-positive prostate tumor.	.	.	.	.	.	.	.	"<sup>177</sup>Lu-PSMA-617 was offered to thirty patients with PSMA-positive prostate tumor. Treatment efficacy was retrospectively assessed by PSA levels with 70% of patients demonstrating a decrease in PSA levels. 18 patients were noted to have PSA decline greater than 25%, while 13 patients had a decline greater than 50%. Six of these patients were restaged using PSMA PET/CT (positron emission tomography/computed tomography), and all six patients had a response rate of more than 50% in SUVmax (maximum standardized uptake value) of the tumor."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	4.9 months	months	.	.	.	62 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles (2-5)	.	.	A single center retrospective analysis studied 62 men with mCRPC who were treated with <sup>177</sup>Lu-PSMA-617. A median of 3 treatment cycles (2-5) were administered over 4 weeks. Progression-free survival and overall survival were 4.9 months (2.4-9.6) and 17.2 months (6-26.4) respectively. Greater than 50% PSA response was found in 58.7% of patients (p < 0.004).	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	17.2 months	months	.	.	.	62 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles (2-5)	.	.	A single center retrospective analysis studied 62 men with mCRPC who were treated with <sup>177</sup>Lu-PSMA-617. A median of 3 treatment cycles (2-5) were administered over 4 weeks. Progression-free survival and overall survival were 4.9 months (2.4-9.6) and 17.2 months (6-26.4) respectively. Greater than 50% PSA response was found in 58.7% of patients (p < 0.004).	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	58.70%	%	.	.	.	62 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles (2-5)	.	.	A single center retrospective analysis studied 62 men with mCRPC who were treated with <sup>177</sup>Lu-PSMA-617. A median of 3 treatment cycles (2-5) were administered over 4 weeks. Progression-free survival and overall survival were 4.9 months (2.4-9.6) and 17.2 months (6-26.4) respectively. Greater than 50% PSA response was found in 58.7% of patients (p < 0.004).	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	56.0 weeks	weeks	.	.	.	104 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles (1-8 cycles)	.	.	A total of 104 patients with mCRPC who were previously treated with one line of chemotherapy (docetaxel and/or cabazitaxel) and at least one of antihormonal therapies (enzalutamide and/or abiraterone) were retrospectively studied after being treated with <sup>177</sup>Lu-PSMA-617 RLT. A median of three cycles were administered (1-8 cycles). Results of the study noted a median overall survival of 56.0 weeks (95% CI: 50.5-61.5) and PSA decline >50% in 33% patients after receiving first cycle of treatment.	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	33.00%	%	.	.	.	104 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles (1-8 cycles)	.	.	A total of 104 patients with mCRPC who were previously treated with one line of chemotherapy (docetaxel and/or cabazitaxel) and at least one of antihormonal therapies (enzalutamide and/or abiraterone) were retrospectively studied after being treated with <sup>177</sup>Lu-PSMA-617 RLT. A median of three cycles were administered (1-8 cycles). Results of the study noted a median overall survival of 56.0 weeks (95% CI: 50.5-61.5) and PSA decline >50% in 33% patients after receiving first cycle of treatment.	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	8.70%	%	.	.	.	36 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	.	.	"A retrospective single center study looked at therapeutic outcomes of <sup>177</sup>Lu-PSMA-617 in mCRPC based on post-treatment imaging findings. 36 patients (aged 67 &plusmn; 8.8 years) were included out of which 23 received 2 cycles of treatment. Eleven patients (47.8%) were considered responsive in the post-therapeutic scans by <sup>177</sup>Lu-PSMA-617, two of which experienced complete response. Nine (39.1%) patients had stable disease while three (13%) experienced disease progression."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	39.10%	%	.	.	.	36 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	.	.	"A retrospective single center study looked at therapeutic outcomes of <sup>177</sup>Lu-PSMA-617 in mCRPC based on post-treatment imaging findings. 36 patients (aged 67 &plusmn; 8.8 years) were included out of which 23 received 2 cycles of treatment. Eleven patients (47.8%) were considered responsive in the post-therapeutic scans by <sup>177</sup>Lu-PSMA-617, two of which experienced complete response. Nine (39.1%) patients had stable disease while three (13%) experienced disease progression."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	13%	%	.	.	.	36 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles	.	.	"A retrospective single center study looked at therapeutic outcomes of <sup>177</sup>Lu-PSMA-617 in mCRPC based on post-treatment imaging findings. 36 patients (aged 67 &plusmn; 8.8 years) were included out of which 23 received 2 cycles of treatment. Eleven patients (47.8%) were considered responsive in the post-therapeutic scans by <sup>177</sup>Lu-PSMA-617, two of which experienced complete response. Nine (39.1%) patients had stable disease while three (13%) experienced disease progression."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	16 months	months	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-4 cycles	.	.	"Another retrospective study evaluated 56 mCPRC patients with a median age of 69.5 (range 55-84) who received one to four cycles of <sup>177</sup>Lu-PSMA-617. Biochemical response was defined using Prostate Cancer Working Group Criteria 3 (PCWG3). A total of 139 cycles of treatment were performed with a decline of greater than 50% in 54% of patients and any PSA decline in 65% of patients. Estimated median overall survival was 16 months versus 14 months in the chemotherapy alone group. Longer OS was observed in patients with a PSA decline of >50%, a baseline ALP level <220 U/l, more than two cycles of treatment, and cumulative activity of greater than 15 GBq."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	54.00%	%	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-4 cycles	.	.	"Another retrospective study evaluated 56 mCPRC patients with a median age of 69.5 (range 55-84) who received one to four cycles of <sup>177</sup>Lu-PSMA-617. Biochemical response was defined using Prostate Cancer Working Group Criteria 3 (PCWG3). A total of 139 cycles of treatment were performed with a decline of greater than 50% in 54% of patients and any PSA decline in 65% of patients. Estimated median overall survival was 16 months versus 14 months in the chemotherapy alone group. Longer OS was observed in patients with a PSA decline of >50%, a baseline ALP level <220 U/l, more than two cycles of treatment, and cumulative activity of greater than 15 GBq."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	65%	%	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-4 cycles	.	.	"Another retrospective study evaluated 56 mCPRC patients with a median age of 69.5 (range 55-84) who received one to four cycles of <sup>177</sup>Lu-PSMA-617. Biochemical response was defined using Prostate Cancer Working Group Criteria 3 (PCWG3). A total of 139 cycles of treatment were performed with a decline of greater than 50% in 54% of patients and any PSA decline in 65% of patients. Estimated median overall survival was 16 months versus 14 months in the chemotherapy alone group. Longer OS was observed in patients with a PSA decline of >50%, a baseline ALP level <220 U/l, more than two cycles of treatment, and cumulative activity of greater than 15 GBq."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	33.00%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 cycles	180 mCi	.	"A study sought to analyze the prognostic significance of monitoring PSA levels during <sup>177</sup>Lu-PSMA-617 treatment. The study included thirty mCPRC patients who had baseline Ga-68 PSMA PET/CT prior to undergoing <sup>177</sup>Lu-PSMA-617 treatment. Patients were treated with a fixed dose of 180 mCi of <sup>177</sup>Lu-PSMA-617 every six to eight weeks. A total of 171 cycles of treatment were administered with a median of four cycles per patients (range 3-7). A PSA decline greater than 50% was seen in 33% of patients after one cycle of treatment and increased to 43% of patients at the conclusion of the last cycle of treatment. Of the 20 patients who did not have a 50% reduction in PSA levels after the first cycle, four of these patients eventually had a PSA decline of greater than 50% after the conclusion of the last cycle of treatment. The median OS was statistically significant in those who had a greater than 50% decline in PSA level 21 &plusmn; 10 (95% CI: 1.2-40.7) compared to those who did not 8.0 &plusmn; 2.6 (95% CI: 2.7-13.2) months (p = 0.012). Any PSA decline was seen in 50% of patients after just one cycle of treatment and remained stable at 46% of patients at the conclusion of treatment, but did not have a statistically significant impact on median OS; however it was significant for any PSA decline after the last cycle of treatment (13 &plusmn; 1, 95% CI: 10.9-15 months for responders versus 6.0 &plusmn; 1.9, 95% CI: 2.2-9.7 months for non-responders)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	43.00%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	180 mCi	.	"A study sought to analyze the prognostic significance of monitoring PSA levels during <sup>177</sup>Lu-PSMA-617 treatment. The study included thirty mCPRC patients who had baseline Ga-68 PSMA PET/CT prior to undergoing <sup>177</sup>Lu-PSMA-617 treatment. Patients were treated with a fixed dose of 180 mCi of <sup>177</sup>Lu-PSMA-617 every six to eight weeks. A total of 171 cycles of treatment were administered with a median of four cycles per patients (range 3-7). A PSA decline greater than 50% was seen in 33% of patients after one cycle of treatment and increased to 43% of patients at the conclusion of the last cycle of treatment. Of the 20 patients who did not have a 50% reduction in PSA levels after the first cycle, four of these patients eventually had a PSA decline of greater than 50% after the conclusion of the last cycle of treatment. The median OS was statistically significant in those who had a greater than 50% decline in PSA level 21 &plusmn; 10 (95% CI: 1.2-40.7) compared to those who did not 8.0 &plusmn; 2.6 (95% CI: 2.7-13.2) months (p = 0.012). Any PSA decline was seen in 50% of patients after just one cycle of treatment and remained stable at 46% of patients at the conclusion of treatment, but did not have a statistically significant impact on median OS; however it was significant for any PSA decline after the last cycle of treatment (13 &plusmn; 1, 95% CI: 10.9-15 months for responders versus 6.0 &plusmn; 1.9, 95% CI: 2.2-9.7 months for non-responders)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	50%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 cycles	180 mCi	.	"A study sought to analyze the prognostic significance of monitoring PSA levels during <sup>177</sup>Lu-PSMA-617 treatment. The study included thirty mCPRC patients who had baseline Ga-68 PSMA PET/CT prior to undergoing <sup>177</sup>Lu-PSMA-617 treatment. Patients were treated with a fixed dose of 180 mCi of <sup>177</sup>Lu-PSMA-617 every six to eight weeks. A total of 171 cycles of treatment were administered with a median of four cycles per patients (range 3-7). A PSA decline greater than 50% was seen in 33% of patients after one cycle of treatment and increased to 43% of patients at the conclusion of the last cycle of treatment. Of the 20 patients who did not have a 50% reduction in PSA levels after the first cycle, four of these patients eventually had a PSA decline of greater than 50% after the conclusion of the last cycle of treatment. The median OS was statistically significant in those who had a greater than 50% decline in PSA level 21 &plusmn; 10 (95% CI: 1.2-40.7) compared to those who did not 8.0 &plusmn; 2.6 (95% CI: 2.7-13.2) months (p = 0.012). Any PSA decline was seen in 50% of patients after just one cycle of treatment and remained stable at 46% of patients at the conclusion of treatment, but did not have a statistically significant impact on median OS; however it was significant for any PSA decline after the last cycle of treatment (13 &plusmn; 1, 95% CI: 10.9-15 months for responders versus 6.0 &plusmn; 1.9, 95% CI: 2.2-9.7 months for non-responders)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	46%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	180 mCi	.	"A study sought to analyze the prognostic significance of monitoring PSA levels during <sup>177</sup>Lu-PSMA-617 treatment. The study included thirty mCPRC patients who had baseline Ga-68 PSMA PET/CT prior to undergoing <sup>177</sup>Lu-PSMA-617 treatment. Patients were treated with a fixed dose of 180 mCi of <sup>177</sup>Lu-PSMA-617 every six to eight weeks. A total of 171 cycles of treatment were administered with a median of four cycles per patients (range 3-7). A PSA decline greater than 50% was seen in 33% of patients after one cycle of treatment and increased to 43% of patients at the conclusion of the last cycle of treatment. Of the 20 patients who did not have a 50% reduction in PSA levels after the first cycle, four of these patients eventually had a PSA decline of greater than 50% after the conclusion of the last cycle of treatment. The median OS was statistically significant in those who had a greater than 50% decline in PSA level 21 &plusmn; 10 (95% CI: 1.2-40.7) compared to those who did not 8.0 &plusmn; 2.6 (95% CI: 2.7-13.2) months (p = 0.012). Any PSA decline was seen in 50% of patients after just one cycle of treatment and remained stable at 46% of patients at the conclusion of treatment, but did not have a statistically significant impact on median OS; however it was significant for any PSA decline after the last cycle of treatment (13 &plusmn; 1, 95% CI: 10.9-15 months for responders versus 6.0 &plusmn; 1.9, 95% CI: 2.2-9.7 months for non-responders)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	48.00%	%	.	.	.	24 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-4 cycles	.	.	"A retrospective study reviewed 24 mCPRC patients with a median age of 81.7 (range 75.1-91.9 years old) and median of four prior lines of treatments who were treated with <sup>177</sup>Lu-PSMA-617. 54% of patients had bone and lymph node metastasis. Primary endpoints were response, which was defined as a decrease in PSA level over 50% from baseline and toxicity. Patients were treated with one to four cycles. A PSA decline over 50% was seen in 48% (n = 11) of patients."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	18-month overall survival (OS)	63.80%	%	.	.	.	68 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	3 cycles every six weeks	.	.	"Another study retrospectively examined outcomes in 68 patients with a mean of 71 years of age (range 46-89) who were treated with a mean of three cycles of <sup>177</sup>Lu-PSMA-617 (median of 3, range 1-7 cycles) every six weeks. The 18-month overall survival was 63.8%. Those with a baseline PSA <20 ug/L had a higher 18-month survival estimate (79.9%) versus those with PSA levels greater than 20 ug/L (53.8%, p = < 0.05). Those with an SUVmax greater than 15 had a higher 18-month survival rate of 56% compared to those with SUVmax less than 15 (p = < 0.05). Their study found any decrease in PSA levels after two cycles of treatment was indicative of greater chance of overall survival (p = < 0.01)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	60 weeks	weeks	.	.	.	52 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-3 cycles every eight weeks	.	.	"An additional retrospective study of 52 mCRPC patients (mean age of 70, range 48-87 years) evaluated the PSA response of those treated with <sup>177</sup>Lu-PSMA-617 after one to three cycles of radioligand therapy (RLT) every eight weeks. A total of 190 cycles of RLT (3-6 cycles per patient) were given and 80% of patients showed a decline after the first cycle with 44% of patients showing a PSA response of more than 50%. After the third cycle, 73% of patients showed any PSA decline. The median OS was 60 weeks for all patients and median OS was statistically longer for those who responded with decline in PSA after first cycle compared to those without (68 vs 33 weeks)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	80%	%	.	.	.	52 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 cycles	.	.	"An additional retrospective study of 52 mCRPC patients (mean age of 70, range 48-87 years) evaluated the PSA response of those treated with <sup>177</sup>Lu-PSMA-617 after one to three cycles of radioligand therapy (RLT) every eight weeks. A total of 190 cycles of RLT (3-6 cycles per patient) were given and 80% of patients showed a decline after the first cycle with 44% of patients showing a PSA response of more than 50%. After the third cycle, 73% of patients showed any PSA decline. The median OS was 60 weeks for all patients and median OS was statistically longer for those who responded with decline in PSA after first cycle compared to those without (68 vs 33 weeks)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	44.00%	%	.	.	.	52 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1 cycles	.	.	"An additional retrospective study of 52 mCRPC patients (mean age of 70, range 48-87 years) evaluated the PSA response of those treated with <sup>177</sup>Lu-PSMA-617 after one to three cycles of radioligand therapy (RLT) every eight weeks. A total of 190 cycles of RLT (3-6 cycles per patient) were given and 80% of patients showed a decline after the first cycle with 44% of patients showing a PSA response of more than 50%. After the third cycle, 73% of patients showed any PSA decline. The median OS was 60 weeks for all patients and median OS was statistically longer for those who responded with decline in PSA after first cycle compared to those without (68 vs 33 weeks)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	73%	%	.	.	.	52 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	3 cycles every eight weeks	.	.	"An additional retrospective study of 52 mCRPC patients (mean age of 70, range 48-87 years) evaluated the PSA response of those treated with <sup>177</sup>Lu-PSMA-617 after one to three cycles of radioligand therapy (RLT) every eight weeks. A total of 190 cycles of RLT (3-6 cycles per patient) were given and 80% of patients showed a decline after the first cycle with 44% of patients showing a PSA response of more than 50%. After the third cycle, 73% of patients showed any PSA decline. The median OS was 60 weeks for all patients and median OS was statistically longer for those who responded with decline in PSA after first cycle compared to those without (68 vs 33 weeks)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	3.8 months	months	.	.	.	25 patients with prostate cancer.	.	.	.	.	A median of four cycles	.	.	"Another retrospective study studied 25 patients less than 55 years of age at prostate cancer diagnosis who were treated with a median of four cycles (range 2-6) of <sup>177</sup>Lu-PSMA-617. The median PFS was 3.8 months (95% CI 2.5-5.3) and OS was 8.5 months (95% 6.2-10.8). An initial PSA reduction of greater than 50% was seen in 36% of patients but not associated with OS benefit (p = 0.601). A PSA response greater than 50% at three months was seen in 48% of patients and associated with improvement in OS (16 months, 95% CI 7.4-24.6 versus 4.0 months, 95% CI: 1.1-6.9, p = 0.002). They also used 68Ga-PSMA-PET/CT and correlated imaging response after up to three cycles in 44% of patients. Responders had a longer median PFS (8.7 months, 95% CI 1.3-16.1 vs. 1.9 months, 95% CI 1.7-2.2, p < 0.001) and OS (16.0 months, 95% CI 7.6-24.4 vs. 4.0 months, 95% CI 0.9-7.1; p = 0.002)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	8.5 months	months	.	.	.	25 patients with prostate cancer.	.	.	.	.	A median of four cycles	.	.	"Another retrospective study studied 25 patients less than 55 years of age at prostate cancer diagnosis who were treated with a median of four cycles (range 2-6) of <sup>177</sup>Lu-PSMA-617. The median PFS was 3.8 months (95% CI 2.5-5.3) and OS was 8.5 months (95% 6.2-10.8). An initial PSA reduction of greater than 50% was seen in 36% of patients but not associated with OS benefit (p = 0.601). A PSA response greater than 50% at three months was seen in 48% of patients and associated with improvement in OS (16 months, 95% CI 7.4-24.6 versus 4.0 months, 95% CI: 1.1-6.9, p = 0.002). They also used 68Ga-PSMA-PET/CT and correlated imaging response after up to three cycles in 44% of patients. Responders had a longer median PFS (8.7 months, 95% CI 1.3-16.1 vs. 1.9 months, 95% CI 1.7-2.2, p < 0.001) and OS (16.0 months, 95% CI 7.6-24.4 vs. 4.0 months, 95% CI 0.9-7.1; p = 0.002)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	70%	%	.	.	.	10 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A small two center study was conducted in 2015, which followed ten mCRPC patients treated with <sup>177</sup>Lu-PSMA-617. Response was evaluated by change in PSA. Eight weeks after therapy, seven out of the 10 study subjects, experienced a decline in PSA. Six out of ten patients had a decline more than 30%, while five patients had a decline of more than 50% in their PSA levels. Three patients showed an increase in PSA indicative of progression of disease. Post-treatment PSA levels declined significantly in this study, indicating positive treatment response."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>30% PSA decline	60.00%	%	.	.	.	10 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A small two center study was conducted in 2015, which followed ten mCRPC patients treated with <sup>177</sup>Lu-PSMA-617. Response was evaluated by change in PSA. Eight weeks after therapy, seven out of the 10 study subjects, experienced a decline in PSA. Six out of ten patients had a decline more than 30%, while five patients had a decline of more than 50% in their PSA levels. Three patients showed an increase in PSA indicative of progression of disease. Post-treatment PSA levels declined significantly in this study, indicating positive treatment response."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	50.00%	%	.	.	.	10 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"A small two center study was conducted in 2015, which followed ten mCRPC patients treated with <sup>177</sup>Lu-PSMA-617. Response was evaluated by change in PSA. Eight weeks after therapy, seven out of the 10 study subjects, experienced a decline in PSA. Six out of ten patients had a decline more than 30%, while five patients had a decline of more than 50% in their PSA levels. Three patients showed an increase in PSA indicative of progression of disease. Post-treatment PSA levels declined significantly in this study, indicating positive treatment response."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	5.5 months	months	.	.	.	254 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"The REALITY (REgistry to Assess Outcome and Toxicity of Targeted RadionucLIde TherapY) study was a prospective real world cohort of 254 patients with mCRPC who received <sup>177</sup>Lu-PSMA-617 as experimental salvage therapy after conventional treatments had failed. The primary end points were efficacy, reflected by PSA-PFS, (prostate specific antigen-progression-free survival) OS, (overall survival) and safety which was reflected by the incidence of treatment-related (AEs). Over the entire course of <sup>177</sup>Lu-PSMA-617 RLT (radioligand therapy), 52.0% patients had a greater than 50% decline in their PSA response. At a median (minimum - maximum) follow-up of 14.9 (5.0-64.4) months, the median PSA-PFS was 5.5 (4.4-6.6) months, while the median OS was 14.5 (11.5-17.5) months."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	4 months	months	.	.	.	191 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-5 cycles	.	.	"A real-world study evaluated 191 patients with mCPRC treated with <sup>177</sup>Lu-PSMA-617. Patients had confirmation of PSMA expressing lesions by 68Ga-PSMA-ligand PET/CT. The majority of individuals (90%) had first- and second-line systemic treatment prior to being treated with <sup>177</sup>Lu-PSMA-617. Patients received one to five cycles of treatment and specific endpoints included biochemical response, radiologic response, PSA PFS, and OS. A PSA RR (defined as a decline of &ge;50% in PSA) was found in 56% of patients, and any PSA decline occurred in 75% of patients. The median radiographic progression-free survival was found to be six months (range 3-10), PSA PFS (n = 132) was 4 months (range 3-8), and the overall survival (n = 191) was 12 months (range 5-18)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	14.5 months	months	.	.	.	254 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"The REALITY (REgistry to Assess Outcome and Toxicity of Targeted RadionucLIde TherapY) study was a prospective real world cohort of 254 patients with mCRPC who received <sup>177</sup>Lu-PSMA-617 as experimental salvage therapy after conventional treatments had failed. The primary end points were efficacy, reflected by PSA-PFS, (prostate specific antigen-progression-free survival) OS, (overall survival) and safety which was reflected by the incidence of treatment-related (AEs). Over the entire course of <sup>177</sup>Lu-PSMA-617 RLT (radioligand therapy), 52.0% patients had a greater than 50% decline in their PSA response. At a median (minimum - maximum) follow-up of 14.9 (5.0-64.4) months, the median PSA-PFS was 5.5 (4.4-6.6) months, while the median OS was 14.5 (11.5-17.5) months."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	12 months	months	.	.	.	191 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-5 cycles	.	.	"A real-world study evaluated 191 patients with mCPRC treated with <sup>177</sup>Lu-PSMA-617. Patients had confirmation of PSMA expressing lesions by 68Ga-PSMA-ligand PET/CT. The majority of individuals (90%) had first- and second-line systemic treatment prior to being treated with <sup>177</sup>Lu-PSMA-617. Patients received one to five cycles of treatment and specific endpoints included biochemical response, radiologic response, PSA PFS, and OS. A PSA RR (defined as a decline of &ge;50% in PSA) was found in 56% of patients, and any PSA decline occurred in 75% of patients. The median radiographic progression-free survival was found to be six months (range 3-10), PSA PFS (n = 132) was 4 months (range 3-8), and the overall survival (n = 191) was 12 months (range 5-18)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	62.7 weeks	weeks	.	.	.	21 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 8 weeks	.	.	"Another real-world prospective cohort study included twenty-one treatments refractory mCRPC patients at Bushehr Department of Nuclear Medicine between December 2016 to December 2018 treated with <sup>177</sup>Lu-PSMA-617 every 8 weeks. Patients had to have PSMA secreting lesions detected by PSMA imaging with 68Ga-PSMA PET or <sup>177</sup>Lu/99Tc-PSMA before to undergoing treatment. The mean age of patients was 70.3 &plusmn; 9.6 (range 54-88) with a median of two cycles of treatment (range 1-4). The primary endpoint of the study was to assess biochemical response (BCR), which was defined as a drop in the PSA of more than 50. Additional secondary endpoints included response by ECOG and overall survival. A BCR was seen in 62% of patients. The estimated overall survival was seen to be 62.69 weeks (95% confidence interval: 42.06-83.33) with a median follow-up period of 9 months (range 1-25 months)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	6 months	months	.	.	.	191 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-5 cycles	.	.	"A real-world study evaluated 191 patients with mCPRC treated with <sup>177</sup>Lu-PSMA-617. Patients had confirmation of PSMA expressing lesions by 68Ga-PSMA-ligand PET/CT. The majority of individuals (90%) had first- and second-line systemic treatment prior to being treated with <sup>177</sup>Lu-PSMA-617. Patients received one to five cycles of treatment and specific endpoints included biochemical response, radiologic response, PSA PFS, and OS. A PSA RR (defined as a decline of &ge;50% in PSA) was found in 56% of patients, and any PSA decline occurred in 75% of patients. The median radiographic progression-free survival was found to be six months (range 3-10), PSA PFS (n = 132) was 4 months (range 3-8), and the overall survival (n = 191) was 12 months (range 5-18)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	19%	%	.	.	.	21 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 8 weeks	.	.	"Another real-world prospective cohort study included twenty-one treatments refractory mCRPC patients at Bushehr Department of Nuclear Medicine between December 2016 to December 2018 treated with <sup>177</sup>Lu-PSMA-617 every 8 weeks. Patients had to have PSMA secreting lesions detected by PSMA imaging with 68Ga-PSMA PET or <sup>177</sup>Lu/99Tc-PSMA before to undergoing treatment. The mean age of patients was 70.3 &plusmn; 9.6 (range 54-88) with a median of two cycles of treatment (range 1-4). The primary endpoint of the study was to assess biochemical response (BCR), which was defined as a drop in the PSA of more than 50. Additional secondary endpoints included response by ECOG and overall survival. A BCR was seen in 62% of patients. The estimated overall survival was seen to be 62.69 weeks (95% confidence interval: 42.06-83.33) with a median follow-up period of 9 months (range 1-25 months)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	19%	%	.	.	.	21 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 8 weeks	.	.	"Another real-world prospective cohort study included twenty-one treatments refractory mCRPC patients at Bushehr Department of Nuclear Medicine between December 2016 to December 2018 treated with <sup>177</sup>Lu-PSMA-617 every 8 weeks. Patients had to have PSMA secreting lesions detected by PSMA imaging with 68Ga-PSMA PET or <sup>177</sup>Lu/99Tc-PSMA before to undergoing treatment. The mean age of patients was 70.3 &plusmn; 9.6 (range 54-88) with a median of two cycles of treatment (range 1-4). The primary endpoint of the study was to assess biochemical response (BCR), which was defined as a drop in the PSA of more than 50. Additional secondary endpoints included response by ECOG and overall survival. A BCR was seen in 62% of patients. The estimated overall survival was seen to be 62.69 weeks (95% confidence interval: 42.06-83.33) with a median follow-up period of 9 months (range 1-25 months)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	52.00%	%	.	.	.	254 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"The REALITY (REgistry to Assess Outcome and Toxicity of Targeted RadionucLIde TherapY) study was a prospective real world cohort of 254 patients with mCRPC who received <sup>177</sup>Lu-PSMA-617 as experimental salvage therapy after conventional treatments had failed. The primary end points were efficacy, reflected by PSA-PFS, (prostate specific antigen-progression-free survival) OS, (overall survival) and safety which was reflected by the incidence of treatment-related (AEs). Over the entire course of <sup>177</sup>Lu-PSMA-617 RLT (radioligand therapy), 52.0% patients had a greater than 50% decline in their PSA response. At a median (minimum - maximum) follow-up of 14.9 (5.0-64.4) months, the median PSA-PFS was 5.5 (4.4-6.6) months, while the median OS was 14.5 (11.5-17.5) months."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	56.00%	%	.	.	.	191 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-5 cycles	.	.	"A real-world study evaluated 191 patients with mCPRC treated with <sup>177</sup>Lu-PSMA-617. Patients had confirmation of PSMA expressing lesions by 68Ga-PSMA-ligand PET/CT. The majority of individuals (90%) had first- and second-line systemic treatment prior to being treated with <sup>177</sup>Lu-PSMA-617. Patients received one to five cycles of treatment and specific endpoints included biochemical response, radiologic response, PSA PFS, and OS. A PSA RR (defined as a decline of &ge;50% in PSA) was found in 56% of patients, and any PSA decline occurred in 75% of patients. The median radiographic progression-free survival was found to be six months (range 3-10), PSA PFS (n = 132) was 4 months (range 3-8), and the overall survival (n = 191) was 12 months (range 5-18)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	62.00%	%	.	.	.	21 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Every 8 weeks	.	.	"Another real-world prospective cohort study included twenty-one treatments refractory mCRPC patients at Bushehr Department of Nuclear Medicine between December 2016 to December 2018 treated with <sup>177</sup>Lu-PSMA-617 every 8 weeks. Patients had to have PSMA secreting lesions detected by PSMA imaging with 68Ga-PSMA PET or <sup>177</sup>Lu/99Tc-PSMA before to undergoing treatment. The mean age of patients was 70.3 &plusmn; 9.6 (range 54-88) with a median of two cycles of treatment (range 1-4). The primary endpoint of the study was to assess biochemical response (BCR), which was defined as a drop in the PSA of more than 50. Additional secondary endpoints included response by ECOG and overall survival. A BCR was seen in 62% of patients. The estimated overall survival was seen to be 62.69 weeks (95% confidence interval: 42.06-83.33) with a median follow-up period of 9 months (range 1-25 months)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	8.7 months	months	.	.	Phase 3	581 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"The VISION trial was an international open-label phase 3 trial that assigned 581 mCRPC patients who previously received a novel hormonal agent and chemotherapy to either the treatment group (receiving <sup>177</sup>Lu-PSMA-617 and standard of care) or control group (standard of care alone). Primary end points were progression-free survival, median overall survival, and median follow-up. Median progression-free survival was 8.7 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 3.4 months in the control group (HR for progression or death, 0.40; 99.2% confidence interval, 0.29 to 0.57; P < 0.001). Median overall survival was 15.3 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 11.3 months in the control group (hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P < 0.001). The median follow-up was 20.3 months (95% CI, 19.8 to 21.0) in the <sup>177</sup>Lu-PSMA-617 group and 19.8 months (95% CI, 18.3 to 20.8) in the control group. Secondary end points included median time to the first symptomatic skeletal event or death and PSA level. The median time to the first symptomatic skeletal event or death was 11.5 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 6.8 months in the control group (P < 0.001). The proportions of patients with confirmed decreases in the PSA level of at least 50% and 80% from baseline were higher in the <sup>177</sup>Lu-PSMA-617 group than in the control group."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	4 months	months	.	.	Phase 2	35 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Up to 4 cycles every 8 weeks	6.0-7.4 GBq/cycle	.	"A randomized, parallel group, open label, and non-inferiority phase II trial conducted between 2019 and 2021 studied a group of thirty five chemo-naive patients with mCPRC and high expressing PSMA lesions on 68Ga-PSMA-11 on PET/CT. Patients were randomized in 1:1 ratio to either <sup>177</sup>Lu PSMA-617 (6.0-7.4 GBq/cycle, every 8 weeks, up to 4 cycles) or docetaxel (75 mg/m<sup>2</sup>/cycle, every 3 weeks, for up to 10 cycles), with fifteen and twenty patients in each group, respectively. The primary endpoint was best PSA response rate (PSA-RR), which is defined as a &ge; 50% decline in PSA from baseline. The <sup>177</sup>Lu PSMA-617 arm PSA-RR was 60% versus 40% in docetaxel group with a difference in PSA-RR of 20% (95% CI: 1-47, p = 0.025) and met the pre-specified criterion for non-inferiority which was defined as margin of 15% decline in PSA-RR. The PFS rate for <sup>177</sup>Lu PSMA-617 was 30% versus 20% for docetaxel (95% CI: 18-38, p = 0.5). The number of treatment-related adverse events grade 3 or higher occurred less in the <sup>177</sup>Lu PSMA-617 arm than the docetaxel arm (30% versus 50% respectively, p = 0.2)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00274; REF00033	PDC_00029	Metastatic castration-resistant prostate cancer	Patients with progressive metastatic castration-resistant prostate cancer.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	8.7 months	months	.	.	Phase 2	.	.	.	.	.	.	.	.	"The Thera-P trial was a phase II prospective multicenter trial looking at those with mCPRC who progressed after docetaxel chemotherapy and were randomly assigned to <sup>177</sup>Lu PSMA-617 or cabazitaxel. Initial reported results found that those who were treated with <sup>177</sup>Lu PSMA-617 treatment led to improvement in PSA response rate (66% vs 37%), RECIST response rate (49% vs 24%), PFS (HR 0.63), less G3-G4 toxicities (33% vs 53%), and overall better patient reported outcomes."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	7.5 months	months	.	.	Phase 2	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"Up to 4 cycles (median number of 3 cycles, range 2-5) every eight to twelve weeks"	.	.	"A phase II study followed forty patients with PET/CT-68Ga-PSMA positive mCRPC treated with <sup>177</sup>Lu PSMA-617. <sup>177</sup>Lu PSMA-617 was given for up to four cycles (median number of three cycles, range 2-5) every eight to twelve weeks. With a median follow-up of 15.5 months (range 6-22 ), 37.5% of patients had a greater than 50% PSA decline and 50% had a PSA decline greater than 30%. The median PFS was 7.5 months (95% CI: 4.8-10.5) and median OS was 12.4 months (95% CI 7.4-20.3 months)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	13.7 months	months	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received <sup>177</sup>Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	15.3 months	months	.	.	Phase 3	581 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"The VISION trial was an international open-label phase 3 trial that assigned 581 mCRPC patients who previously received a novel hormonal agent and chemotherapy to either the treatment group (receiving <sup>177</sup>Lu-PSMA-617 and standard of care) or control group (standard of care alone). Primary end points were progression-free survival, median overall survival, and median follow-up. Median progression-free survival was 8.7 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 3.4 months in the control group (HR for progression or death, 0.40; 99.2% confidence interval, 0.29 to 0.57; P < 0.001). Median overall survival was 15.3 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 11.3 months in the control group (hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P < 0.001). The median follow-up was 20.3 months (95% CI, 19.8 to 21.0) in the <sup>177</sup>Lu-PSMA-617 group and 19.8 months (95% CI, 18.3 to 20.8) in the control group. Secondary end points included median time to the first symptomatic skeletal event or death and PSA level. The median time to the first symptomatic skeletal event or death was 11.5 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 6.8 months in the control group (P < 0.001). The proportions of patients with confirmed decreases in the PSA level of at least 50% and 80% from baseline were higher in the <sup>177</sup>Lu-PSMA-617 group than in the control group."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	16 months	months	.	.	Phase 1/2	31 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles (range: 1-4)	.	.	"A prospective single center phase II study included 31 patients with mCRPC who had progressed despite second-line hormonal therapy and/or docetaxel chemotherapy. The patients underwent an average of two cycles (range 1-4) of <sup>177</sup>Lu-DKFZ-PSMA-617 therapy. The primary endpoints of the study were to determine radiographic progression-free survival (RPFS) using PET/CT scans and overall survival (OS). The treatment response was evaluated based on biochemical response using serum PSA, molecular response using PET/CT scans, and clinical response using VAS (visual analogue scale), AS (analgesic score) and ECOG (Eastern Cooperative Oncology Group) performance status. Biochemical response showed that the mean serum PSA level after three months of initial therapy was 141.75 &plusmn; 187.43 ng/mL (range 2.5-807). The mean serum PSA level three months after the second cycle was 153.07 &plusmn; 204 ng/mL (range 1.34-762). The molecular response estimated by the mean SUVmax (maximum standardized uptake value) of tumor lesions before and after therapy was 56.7 and 18.2 respectively. In two patients it was reduced from 32.67 to 0.38 after <sup>177</sup>Lu-DKFZ-PSMA-617 therapy, thus indicating a complete remission. The clinical response was estimated using the mean VASmax and AS. The pre-therapy VASmax was 7.5 &plusmn; 1, and post-therapy was 3 &plusmn; 0.9 (p < 0.0001), while the mean AS pre-therapy and post therapy was 2.5 &plusmn; 1.09 and 1.8 &plusmn; 0.98 (p = 0.009) respectively, and mean ECOG performance status improved from 2.54 &plusmn; 0.85 to 1.78 &plusmn; 0.92 after completion of therapy (p = 0.001). The median overall survival was 16 months, and progression-free survival was 12 months. 16.1% patients died due to disease during follow-up. This trial particularly highlighted an improvement in the ECOG performance status in patients receiving <sup>177</sup>Lu-DKFZ-PSMA-617 for the treatment of mCRPC."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	50 weeks	weeks	.	.	Phase 2	14 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Up to 3 cycles every six weeks	.	.	"A prospective phase II pilot study enrolled fourteen patients with progressive and symptomatic mCRPC despite taxane and novel anti-androgen therapy to receive up to four cycles of <sup>177</sup>Lu PSMA-617 every six weeks. Ten out of the 14 patients had a mean PSA reduction of 59%, with five patients having over a 50% reduction, and nine patients having over a 30% reduction in PSA levels. At baseline testing, the PSMA PET SUV predicted a reduction in PSA of more than 30%, with an SUV max value of 17 &plusmn; 9 compared to 44 &plusmn; 15 (p < 0.007), and a PSMA SUV mean of 6 &plusmn; 4 compared to 10 &plusmn; 4 (p < 0.04)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	15.3 months	months	.	.	Phase 2	.	.	.	.	.	.	.	.	"The Thera-P trial was a phase II prospective multicenter trial looking at those with mCPRC who progressed after docetaxel chemotherapy and were randomly assigned to <sup>177</sup>Lu PSMA-617 or cabazitaxel. Initial reported results found that those who were treated with <sup>177</sup>Lu PSMA-617 treatment led to improvement in PSA response rate (66% vs 37%), RECIST response rate (49% vs 24%), PFS (HR 0.63), less G3-G4 toxicities (33% vs 53%), and overall better patient reported outcomes."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	13.5 months	months	.	.	Phase 2	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	.	.	"Another single-arm, single-center, phase 2 trial recruited thirty men with mCRPC and progressive disease after receiving standard treatments including taxane-based chemotherapy and second-generation anti-androgen treatment (abiraterone, enzalutamide, or both). They were administered four cycles of <sup>177</sup>Lu-PSMA-617. The primary end points included PSA level, imaging response using bone scan, and PET/CT and quality of life. The PSA decline of greater than or equal to 50% was achieved in 57% of patients. Imaging response using PSMA PET showed a complete response in 10% of patients, a partial response in 30% of patients, and progressive disease in 27% of patients. Cognitive functioning, insomnia, and pain, which were measured using the EORTC-QLQ30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire) and BPI (brief pain inventory) scoring tools showed improvement during treatment compared to baseline, thus indicating improved quality of life."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	12.4 months	months	.	.	Phase 2	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"Up to 4 cycles (median number of 3 cycles, range 2-5) every eight to twelve weeks"	.	.	"A phase II study followed forty patients with PET/CT-68Ga-PSMA positive mCRPC treated with <sup>177</sup>Lu PSMA-617. <sup>177</sup>Lu PSMA-617 was given for up to four cycles (median number of three cycles, range 2-5) every eight to twelve weeks. With a median follow-up of 15.5 months (range 6-22 ), 37.5% of patients had a greater than 50% PSA decline and 50% had a PSA decline greater than 30%. The median PFS was 7.5 months (95% CI: 4.8-10.5) and median OS was 12.4 months (95% CI 7.4-20.3 months)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	9.20%	%	.	.	Phase 3	581 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"The VISION trial was an international open-label phase 3 trial that assigned 581 mCRPC patients who previously received a novel hormonal agent and chemotherapy to either the treatment group (receiving <sup>177</sup>Lu-PSMA-617 and standard of care) or control group (standard of care alone). Primary end points were progression-free survival, median overall survival, and median follow-up. Median progression-free survival was 8.7 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 3.4 months in the control group (HR for progression or death, 0.40;99.2% confidence interval, 0.29 to 0.57;P < 0.001). Median overall survival was 15.3 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 11.3 months in the control group (hazard ratio for death, 0.62;95% CI, 0.52 to 0.74;P < 0.001). The median follow-up was 20.3 months (95% CI, 19.8 to 21.0) in the <sup>177</sup>Lu-PSMA-617 group and 19.8 months (95% CI, 18.3 to 20.8) in the control group. Secondary end points included median time to the first symptomatic skeletal event or death and PSA level. The median time to the first symptomatic skeletal event or death was 11.5 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 6.8 months in the control group (P < 0.001). The proportions of patients with confirmed decreases in the PSA level of at least 50% and 80% from baseline were higher in the <sup>177</sup>Lu-PSMA-617 group than in the control group."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	41.80%	%	.	.	Phase 3	581 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"The VISION trial was an international open-label phase 3 trial that assigned 581 mCRPC patients who previously received a novel hormonal agent and chemotherapy to either the treatment group (receiving <sup>177</sup>Lu-PSMA-617 and standard of care) or control group (standard of care alone). Primary end points were progression-free survival, median overall survival, and median follow-up. Median progression-free survival was 8.7 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 3.4 months in the control group (HR for progression or death, 0.40;99.2% confidence interval, 0.29 to 0.57;P < 0.001). Median overall survival was 15.3 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 11.3 months in the control group (hazard ratio for death, 0.62;95% CI, 0.52 to 0.74;P < 0.001). The median follow-up was 20.3 months (95% CI, 19.8 to 21.0) in the <sup>177</sup>Lu-PSMA-617 group and 19.8 months (95% CI, 18.3 to 20.8) in the control group. Secondary end points included median time to the first symptomatic skeletal event or death and PSA level. The median time to the first symptomatic skeletal event or death was 11.5 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 6.8 months in the control group (P < 0.001). The proportions of patients with confirmed decreases in the PSA level of at least 50% and 80% from baseline were higher in the <sup>177</sup>Lu-PSMA-617 group than in the control group."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	29%	%	.	.	Phase 2	14 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Up to 3 cycles every six weeks	.	.	"A prospective phase II pilot study enrolled fourteen patients with progressive and symptomatic mCRPC despite taxane and novel anti-androgen therapy to receive up to four cycles of <sup>177</sup>Lu PSMA-617 every six weeks. Ten out of the 14 patients had a mean PSA reduction of 59%, with five patients having over a 50% reduction, and nine patients having over a 30% reduction in PSA levels. At baseline testing, the PSMA PET SUV predicted a reduction in PSA of more than 30%, with an SUV max value of 17 &plusmn; 9 compared to 44 &plusmn; 15 (p < 0.007), and a PSMA SUV mean of 6 &plusmn; 4 compared to 10 &plusmn; 4 (p < 0.04)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	14%	%	.	.	Phase 2	14 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Up to 3 cycles every six weeks	.	.	"A prospective phase II pilot study enrolled fourteen patients with progressive and symptomatic mCRPC despite taxane and novel anti-androgen therapy to receive up to four cycles of <sup>177</sup>Lu PSMA-617 every six weeks. Ten out of the 14 patients had a mean PSA reduction of 59%, with five patients having over a 50% reduction, and nine patients having over a 30% reduction in PSA levels. At baseline testing, the PSMA PET SUV predicted a reduction in PSA of more than 30%, with an SUV max value of 17 &plusmn; 9 compared to 44 &plusmn; 15 (p < 0.007), and a PSMA SUV mean of 6 &plusmn; 4 compared to 10 &plusmn; 4 (p < 0.04)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	29%	%	.	.	Phase 2	14 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Up to 3 cycles every six weeks	.	.	"A prospective phase II pilot study enrolled fourteen patients with progressive and symptomatic mCRPC despite taxane and novel anti-androgen therapy to receive up to four cycles of <sup>177</sup>Lu PSMA-617 every six weeks. Ten out of the 14 patients had a mean PSA reduction of 59%, with five patients having over a 50% reduction, and nine patients having over a 30% reduction in PSA levels. At baseline testing, the PSMA PET SUV predicted a reduction in PSA of more than 30%, with an SUV max value of 17 &plusmn; 9 compared to 44 &plusmn; 15 (p < 0.007), and a PSMA SUV mean of 6 &plusmn; 4 compared to 10 &plusmn; 4 (p < 0.04)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	39%	%	.	.	Phase 2	35 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Up to 4 cycles every 8 weeks	6.0-7.4 GBq/cycle	.	"A randomized, parallel group, open label, and non-inferiority phase II trial conducted between 2019 and 2021 studied a group of thirty five chemo-naive patients with mCPRC and high expressing PSMA lesions on 68Ga-PSMA-11 on PET/CT. Patients were randomized in 1:1 ratio to either <sup>177</sup>Lu PSMA-617 (6.0-7.4 GBq/cycle, every 8 weeks, up to 4 cycles) or docetaxel (75 mg/m<sup>2</sup>/cycle, every 3 weeks, for up to 10 cycles), with fifteen and twenty patients in each group, respectively. The primary endpoint was best PSA response rate (PSA-RR), which is defined as a &ge; 50% decline in PSA from baseline. The <sup>177</sup>Lu PSMA-617 arm PSA-RR was 60% versus 40% in docetaxel group with a difference in PSA-RR of 20% (95% CI:1-47, p = 0.025) and met the pre-specified criterion for non-inferiority which was defined as margin of 15% decline in PSA-RR. The PFS rate for <sup>177</sup>Lu PSMA-617 was 30% versus 20% for docetaxel (95% CI:18-38, p = 0.5). The number of treatment-related adverse events grade 3 or higher occurred less in the <sup>177</sup>Lu PSMA-617 arm than the docetaxel arm (30% versus 50% respectively, p = 0.2)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	46%	%	.	.	Phase 2	.	.	.	.	.	.	.	.	"The Thera-P trial was a phase II prospective multicenter trial looking at those with mCPRC who progressed after docetaxel chemotherapy and were randomly assigned to <sup>177</sup>Lu PSMA-617 or cabazitaxel. Initial reported results found that those who were treated with <sup>177</sup>Lu PSMA-617 treatment led to improvement in PSA response rate (66% vs 37%), RECIST response rate (49% vs 24%), PFS (HR 0.63), less G3-G4 toxicities (33% vs 53%), and overall better patient reported outcomes."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	29%	%	.	.	Phase 2	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	.	.	"Another single-arm, single-center, phase 2 trial recruited thirty men with mCRPC and progressive disease after receiving standard treatments including taxane-based chemotherapy and second-generation anti-androgen treatment (abiraterone, enzalutamide, or both). They were administered four cycles of <sup>177</sup>Lu-PSMA-617. The primary end points included PSA level, imaging response using bone scan, and PET/CT and quality of life. The PSA decline of greater than or equal to 50% was achieved in 57% of patients. Imaging response using PSMA PET showed a complete response in 10% of patients, a partial response in 30% of patients, and progressive disease in 27% of patients. Cognitive functioning, insomnia, and pain, which were measured using the EORTC-QLQ30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire) and BPI (brief pain inventory) scoring tools showed improvement during treatment compared to baseline, thus indicating improved quality of life."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	53%	%	.	.	Phase 2	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	.	.	"Another single-arm, single-center, phase 2 trial recruited thirty men with mCRPC and progressive disease after receiving standard treatments including taxane-based chemotherapy and second-generation anti-androgen treatment (abiraterone, enzalutamide, or both). They were administered four cycles of <sup>177</sup>Lu-PSMA-617. The primary end points included PSA level, imaging response using bone scan, and PET/CT and quality of life. The PSA decline of greater than or equal to 50% was achieved in 57% of patients. Imaging response using PSMA PET showed a complete response in 10% of patients, a partial response in 30% of patients, and progressive disease in 27% of patients. Cognitive functioning, insomnia, and pain, which were measured using the EORTC-QLQ30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire) and BPI (brief pain inventory) scoring tools showed improvement during treatment compared to baseline, thus indicating improved quality of life."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	20%	%	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received <sup>177</sup>Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	52%	%	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received <sup>177</sup>Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	28%	%	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received <sup>177</sup>Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Maximum standardized uptake value (SUV<sub>max</sub>)	56.7	.	.	.	Phase 1/2	31 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles (range: 1-4)	.	.	"A prospective single center phase II study included 31 patients with mCRPC who had progressed despite second-line hormonal therapy and/or docetaxel chemotherapy. The patients underwent an average of two cycles (range 1-4) of <sup>177</sup>Lu-DKFZ-PSMA-617 therapy. The primary endpoints of the study were to determine radiographic progression-free survival (RPFS) using PET/CT scans and overall survival (OS). The treatment response was evaluated based on biochemical response using serum PSA, molecular response using PET/CT scans, and clinical response using VAS (visual analogue scale), AS (analgesic score) and ECOG (Eastern Cooperative Oncology Group) performance status. Biochemical response showed that the mean serum PSA level after three months of initial therapy was 141.75 &plusmn; 187.43 ng/mL (range 2.5-807). The mean serum PSA level three months after the second cycle was 153.07 &plusmn; 204 ng/mL (range 1.34-762). The molecular response estimated by the mean SUVmax (maximum standardized uptake value) of tumor lesions before and after therapy was 56.7 and 18.2 respectively. In two patients it was reduced from 32.67 to 0.38 after <sup>177</sup>Lu-DKFZ-PSMA-617 therapy, thus indicating a complete remission. The clinical response was estimated using the mean VASmax and AS. The pre-therapy VASmax was 7.5 &plusmn; 1, and post-therapy was 3 &plusmn; 0.9 (p < 0.0001), while the mean AS pre-therapy and post therapy was 2.5 &plusmn; 1.09 and 1.8 &plusmn; 0.98 (p = 0.009) respectively, and mean ECOG performance status improved from 2.54 &plusmn; 0.85 to 1.78 &plusmn; 0.92 after completion of therapy (p = 0.001). The median overall survival was 16 months, and progression-free survival was 12 months. 16.1% patients died due to disease during follow-up. This trial particularly highlighted an improvement in the ECOG performance status in patients receiving <sup>177</sup>Lu-DKFZ-PSMA-617 for the treatment of mCRPC."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Maximum standardized uptake value (SUV<sub>max</sub>)	18.2	.	.	.	Phase 1/2	31 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 cycles (range: 1-4)	.	.	"A prospective single center phase II study included 31 patients with mCRPC who had progressed despite second-line hormonal therapy and/or docetaxel chemotherapy. The patients underwent an average of two cycles (range 1-4) of <sup>177</sup>Lu-DKFZ-PSMA-617 therapy. The primary endpoints of the study were to determine radiographic progression-free survival (RPFS) using PET/CT scans and overall survival (OS). The treatment response was evaluated based on biochemical response using serum PSA, molecular response using PET/CT scans, and clinical response using VAS (visual analogue scale), AS (analgesic score) and ECOG (Eastern Cooperative Oncology Group) performance status. Biochemical response showed that the mean serum PSA level after three months of initial therapy was 141.75 &plusmn; 187.43 ng/mL (range 2.5-807). The mean serum PSA level three months after the second cycle was 153.07 &plusmn; 204 ng/mL (range 1.34-762). The molecular response estimated by the mean SUVmax (maximum standardized uptake value) of tumor lesions before and after therapy was 56.7 and 18.2 respectively. In two patients it was reduced from 32.67 to 0.38 after <sup>177</sup>Lu-DKFZ-PSMA-617 therapy, thus indicating a complete remission. The clinical response was estimated using the mean VASmax and AS. The pre-therapy VASmax was 7.5 &plusmn; 1, and post-therapy was 3 &plusmn; 0.9 (p < 0.0001), while the mean AS pre-therapy and post therapy was 2.5 &plusmn; 1.09 and 1.8 &plusmn; 0.98 (p = 0.009) respectively, and mean ECOG performance status improved from 2.54 &plusmn; 0.85 to 1.78 &plusmn; 0.92 after completion of therapy (p = 0.001). The median overall survival was 16 months, and progression-free survival was 12 months. 16.1% patients died due to disease during follow-up. This trial particularly highlighted an improvement in the ECOG performance status in patients receiving <sup>177</sup>Lu-DKFZ-PSMA-617 for the treatment of mCRPC."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	35.70%	%	.	.	.	50 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles	.	.	"Fifty patients were studied prospectively with PSMA-avid prostate cancer metastases who underwent a median of three cycles (range 1-4) of <sup>177</sup>Lu PSMA-617 therapy. Nine were deemed <sup>177</sup>Lu PSMA-617 refractory prior to death with a total of twelve deaths in the study. A PSA decline was noted in 23 patients, with 11 patients having a PSA decline of &ge;50% after the first cycle of treatment. 12 patients had a PSA decline of <50% ranging from 11.3 to 43.5%. The remaining 23 patients experienced a PSA increase after the first <sup>177</sup>Lu PSMA-617 cycle (range 19.7-100%)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	7.10%	%	.	.	.	50 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles	.	.	"Fifty patients were studied prospectively with PSMA-avid prostate cancer metastases who underwent a median of three cycles (range 1-4) of <sup>177</sup>Lu PSMA-617 therapy. Nine were deemed <sup>177</sup>Lu PSMA-617 refractory prior to death with a total of twelve deaths in the study. A PSA decline was noted in 23 patients, with 11 patients having a PSA decline of &ge;50% after the first cycle of treatment. 12 patients had a PSA decline of <50% ranging from 11.3 to 43.5%. The remaining 23 patients experienced a PSA increase after the first <sup>177</sup>Lu PSMA-617 cycle (range 19.7-100%)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	57.10%	%	.	.	.	50 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles	.	.	"Fifty patients were studied prospectively with PSMA-avid prostate cancer metastases who underwent a median of three cycles (range 1-4) of <sup>177</sup>Lu PSMA-617 therapy. Nine were deemed <sup>177</sup>Lu PSMA-617 refractory prior to death with a total of twelve deaths in the study. A PSA decline was noted in 23 patients, with 11 patients having a PSA decline of &ge;50% after the first cycle of treatment. 12 patients had a PSA decline of <50% ranging from 11.3 to 43.5%. The remaining 23 patients experienced a PSA increase after the first <sup>177</sup>Lu PSMA-617 cycle (range 19.7-100%)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	10%	%	.	.	Phase 2	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	.	.	"Another single-arm, single-center, phase 2 trial recruited thirty men with mCRPC and progressive disease after receiving standard treatments including taxane-based chemotherapy and second-generation anti-androgen treatment (abiraterone, enzalutamide, or both). They were administered four cycles of <sup>177</sup>Lu-PSMA-617. The primary end points included PSA level, imaging response using bone scan, and PET/CT and quality of life. The PSA decline of greater than or equal to 50% was achieved in 57% of patients. Imaging response using PSMA PET showed a complete response in 10% of patients, a partial response in 30% of patients, and progressive disease in 27% of patients. Cognitive functioning, insomnia, and pain, which were measured using the EORTC-QLQ30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire) and BPI (brief pain inventory) scoring tools showed improvement during treatment compared to baseline, thus indicating improved quality of life."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	30%	%	.	.	Phase 2	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	.	.	"Another single-arm, single-center, phase 2 trial recruited thirty men with mCRPC and progressive disease after receiving standard treatments including taxane-based chemotherapy and second-generation anti-androgen treatment (abiraterone, enzalutamide, or both). They were administered four cycles of <sup>177</sup>Lu-PSMA-617. The primary end points included PSA level, imaging response using bone scan, and PET/CT and quality of life. The PSA decline of greater than or equal to 50% was achieved in 57% of patients. Imaging response using PSMA PET showed a complete response in 10% of patients, a partial response in 30% of patients, and progressive disease in 27% of patients. Cognitive functioning, insomnia, and pain, which were measured using the EORTC-QLQ30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire) and BPI (brief pain inventory) scoring tools showed improvement during treatment compared to baseline, thus indicating improved quality of life."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	27%	%	.	.	Phase 2	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	.	.	"Another single-arm, single-center, phase 2 trial recruited thirty men with mCRPC and progressive disease after receiving standard treatments including taxane-based chemotherapy and second-generation anti-androgen treatment (abiraterone, enzalutamide, or both). They were administered four cycles of <sup>177</sup>Lu-PSMA-617. The primary end points included PSA level, imaging response using bone scan, and PET/CT and quality of life. The PSA decline of greater than or equal to 50% was achieved in 57% of patients. Imaging response using PSMA PET showed a complete response in 10% of patients, a partial response in 30% of patients, and progressive disease in 27% of patients. Cognitive functioning, insomnia, and pain, which were measured using the EORTC-QLQ30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire) and BPI (brief pain inventory) scoring tools showed improvement during treatment compared to baseline, thus indicating improved quality of life."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Maximum standardized uptake value (SUV<sub>max</sub>)	37.5	.	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received <sup>177</sup>Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Maximum standardized uptake value (SUV<sub>max</sub>)	15.7	.	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received <sup>177</sup>Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	56%	%	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received <sup>177</sup>Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	8%	%	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received <sup>177</sup>Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	36%	%	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received <sup>177</sup>Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	46.00%	%	.	.	Phase 3	581 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"The VISION trial was an international open-label phase 3 trial that assigned 581 mCRPC patients who previously received a novel hormonal agent and chemotherapy to either the treatment group (receiving <sup>177</sup>Lu-PSMA-617 and standard of care) or control group (standard of care alone). Primary end points were progression-free survival, median overall survival, and median follow-up. Median progression-free survival was 8.7 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 3.4 months in the control group (HR for progression or death, 0.40; 99.2% confidence interval, 0.29 to 0.57; P < 0.001). Median overall survival was 15.3 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 11.3 months in the control group (hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P < 0.001). The median follow-up was 20.3 months (95% CI, 19.8 to 21.0) in the <sup>177</sup>Lu-PSMA-617 group and 19.8 months (95% CI, 18.3 to 20.8) in the control group. Secondary end points included median time to the first symptomatic skeletal event or death and PSA level. The median time to the first symptomatic skeletal event or death was 11.5 months in the <sup>177</sup>Lu-PSMA-617 group, as compared with 6.8 months in the control group (P < 0.001). The proportions of patients with confirmed decreases in the PSA level of at least 50% and 80% from baseline were higher in the <sup>177</sup>Lu-PSMA-617 group than in the control group."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	50.00%	%	.	.	Phase 2	35 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Up to 4 cycles every 8 weeks	6.0-7.4 GBq/cycle	.	"A randomized, parallel group, open label, and non-inferiority phase II trial conducted between 2019 and 2021 studied a group of thirty five chemo-naive patients with mCPRC and high expressing PSMA lesions on 68Ga-PSMA-11 on PET/CT. Patients were randomized in 1:1 ratio to either <sup>177</sup>Lu PSMA-617 (6.0-7.4 GBq/cycle, every 8 weeks, up to 4 cycles) or docetaxel (75 mg/m<sup>2</sup>/cycle, every 3 weeks, for up to 10 cycles), with fifteen and twenty patients in each group, respectively. The primary endpoint was best PSA response rate (PSA-RR), which is defined as a &ge; 50% decline in PSA from baseline. The <sup>177</sup>Lu PSMA-617 arm PSA-RR was 60% versus 40% in docetaxel group with a difference in PSA-RR of 20% (95% CI: 1-47, p = 0.025) and met the pre-specified criterion for non-inferiority which was defined as margin of 15% decline in PSA-RR. The PFS rate for <sup>177</sup>Lu PSMA-617 was 30% versus 20% for docetaxel (95% CI: 18-38, p = 0.5). The number of treatment-related adverse events grade 3 or higher occurred less in the <sup>177</sup>Lu PSMA-617 arm than the docetaxel arm (30% versus 50% respectively, p = 0.2)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	64.00%	%	.	.	Phase 2	.	.	.	.	.	.	.	.	"The Thera-P trial was a phase II prospective multicenter trial looking at those with mCPRC who progressed after docetaxel chemotherapy and were randomly assigned to <sup>177</sup>Lu PSMA-617 or cabazitaxel. Initial reported results found that those who were treated with <sup>177</sup>Lu PSMA-617 treatment led to improvement in PSA response rate (66% vs 37%), RECIST response rate (49% vs 24%), PFS (HR 0.63), less G3-G4 toxicities (33% vs 53%), and overall better patient reported outcomes."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	44.90%	%	.	.	.	50 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	A median of 3 cycles	.	.	"Fifty patients were studied prospectively with PSMA-avid prostate cancer metastases who underwent a median of three cycles (range 1-4) of <sup>177</sup>Lu PSMA-617 therapy. Nine were deemed <sup>177</sup>Lu PSMA-617 refractory prior to death with a total of twelve deaths in the study. A PSA decline was noted in 23 patients, with 11 patients having a PSA decline of &ge;50% after the first cycle of treatment. 12 patients had a PSA decline of <50% ranging from 11.3 to 43.5%. The remaining 23 patients experienced a PSA increase after the first <sup>177</sup>Lu PSMA-617 cycle (range 19.7-100%)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	57.00%	%	.	.	Phase 2	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	4 cycles	.	.	"Another single-arm, single-center, phase 2 trial recruited thirty men with mCRPC and progressive disease after receiving standard treatments including taxane-based chemotherapy and second-generation anti-androgen treatment (abiraterone, enzalutamide, or both). They were administered four cycles of <sup>177</sup>Lu-PSMA-617. The primary end points included PSA level, imaging response using bone scan, and PET/CT and quality of life. The PSA decline of greater than or equal to 50% was achieved in 57% of patients. Imaging response using PSMA PET showed a complete response in 10% of patients, a partial response in 30% of patients, and progressive disease in 27% of patients. Cognitive functioning, insomnia, and pain, which were measured using the EORTC-QLQ30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire) and BPI (brief pain inventory) scoring tools showed improvement during treatment compared to baseline, thus indicating improved quality of life."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	37.50%	%	.	.	Phase 2	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	"Up to 4 cycles (median number of 3 cycles, range 2-5) every eight to twelve weeks"	.	.	"A phase II study followed forty patients with PET/CT-68Ga-PSMA positive mCRPC treated with <sup>177</sup>Lu PSMA-617. <sup>177</sup>Lu PSMA-617 was given for up to four cycles (median number of three cycles, range 2-5) every eight to twelve weeks. With a median follow-up of 15.5 months (range 6-22 ), 37.5% of patients had a greater than 50% PSA decline and 50% had a PSA decline greater than 30%. The median PFS was 7.5 months (95% CI: 4.8-10.5) and median OS was 12.4 months (95% CI 7.4-20.3 months)."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	58.90%	%	.	.	.	56 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Another prospective trial studied 56 patients with progressive mCRPC and rising PSA levels who then received <sup>177</sup>Lu-PSMA. Clinical efficacy was assessed using the visual analogue scale for pain, PSA levels, median overall survival, and Gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA PET/CT) for objective response. There was a decline in PSA of greater than 80% in 23.2% of patients, a decline of greater than 50% in 58.9%, and a decline of greater than 30% in 66.1% of patients. Progressive disease was noted in 10.7% of patients with a rise in PSA level greater than 25%. 68Ga-PSMA PET/CT prior to PSMA radioligand therapy showed the median SUVmax of the target lesion to be 37.5, which decreased to 15.7 after PSMA RLT. Ga-PSMA PET/CT was used to measure response rates which included a partial remission in 56%, stable disease in 8%, and progressive disease in 36% of patients. The median progression-free survival was 13.7 months, and median overall survival was not reached. PET/CT results showing a decrease in SUV max of the target lesion are indicative of a favorable objective response to Lu-PSMA therapy."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00264	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	45.40%	%	.	.	.	14 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2 or more cycles	.	.	"A prospective trial investigated the efficacy and toxicity of <sup>177</sup>Lu-PSMA-617 in fourteen patients with mCRPC. Biochemical response using PSA level and clinical symptoms were evaluated after two or more cycles of treatment. PSA levels declined in 11 out of 14 (78.6%) patients, with greater than 50% decline in 45.4% patients over a period of 8 weeks. Progressive disease, defined by a PSA increase of 25% or greater occurred in 21.4% patients. The mean serum alkaline phosphatase level declined from 569.5 U/L to 498.4 U/L, but this was not statistically significant (P = 0.17). At baseline, nine patients with bone metastases reported skeletal bone pain. Eight of these patients showed improvement in pain after treatment."	"<sup>177</sup>Lu-PSMA-617 has shown promising results in the treatment of men with mCRPC and is likely to play a significant role in the future of prostate cancer management. Repeatedly, this novel therapy has demonstrated a low toxicity profile and appears to be well tolerated in men with refractory metastatic disease. Both retrospective studies and prospective clinical trials have shown to be an effective option for patients with mCRPC following novel hormonal agents and chemotherapy. A limitation to this review is its retrospective nature, which makes it difficult to compare patient populations, dosing cycles, and dose intensities between studies. Amongst the studies, there is also inherent variation in measurement/biomarkers of response, PSMA imaging modalities used, retrospective vs. prospective designs, and small recruitment size. Nonetheless, this systematic review covers the landmark early studies that led to approval of <sup>177</sup>Lu-PSMA-617 for mCRPC and highlights the promise of this novel prostate cancer treatment."
REF00267	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Drug uptake dose	37.2 cpm/&micro;g	cpm/&micro;g	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	30 min	"<sup>177</sup>Lu-PSMA-617 0.44 nM, 2 MBq/4 ml/dish; PSMA-617 (10 nM)"	.	"Both <sup>177</sup>Lu-PSMA-617 and its non-radioactive precursor, PSMA-617, bind to the PSMA on the cell membrane. Therefore, PSMA-617 could compete with the <sup>177</sup>Lu-PSMA-617- binding to LNCaP cells and, consequently may reduce its cytotoxic effects. However, PSMA-617 concentrations up to 100 nM did not impair the <sup>177</sup>Lu-PSMA-617 uptake into the LNCaP cells (n = 9). Effects of PSMA-617 (10, 50 and 100 nM) (solid columns) on the uptake of <sup>177</sup>Lu-PSMA-617 into LNCaP cells. Empty column, cells treated with vehicle. Results are expressed as the means &plusmn; SD. No significant differences among the groups were found (one-way ANOVA)."	Our results indicate that PSMA-617 inhibits proliferation of PCa cells and potentiates the cell death-promoting effects of <sup>177</sup>Lu-PSMA-617. These findings require further confirmation in vitro and in vivo experiments to study the exact molecular mechanisms associated with the growth-inhibitory effects of PSMA-617 observed in PCa cells in order to test the potential of the simultaneous treatment with PSMA-617 and <sup>177</sup>Lu-PSMA-617 for the translation in a clinical trial.
REF00267	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Drug uptake dose	38 cpm/&micro;g	cpm/&micro;g	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	30 min	"<sup>177</sup>Lu-PSMA-617 0.44 nM, 2 MBq/4 ml/dish; PSMA-617 (10 nM)"	.	"Both <sup>177</sup>Lu-PSMA-617 and its non-radioactive precursor, PSMA-617, bind to the PSMA on the cell membrane. Therefore, PSMA-617 could compete with the <sup>177</sup>Lu-PSMA-617- binding to LNCaP cells and, consequently may reduce its cytotoxic effects. However, PSMA-617 concentrations up to 100 nM did not impair the <sup>177</sup>Lu-PSMA-617 uptake into the LNCaP cells (n = 9). Effects of PSMA-617 (10, 50 and 100 nM) (solid columns) on the uptake of <sup>177</sup>Lu-PSMA-617 into LNCaP cells. Empty column, cells treated with vehicle. Results are expressed as the means &plusmn; SD. No significant differences among the groups were found (one-way ANOVA)."	Our results indicate that PSMA-617 inhibits proliferation of PCa cells and potentiates the cell death-promoting effects of <sup>177</sup>Lu-PSMA-617. These findings require further confirmation in vitro and in vivo experiments to study the exact molecular mechanisms associated with the growth-inhibitory effects of PSMA-617 observed in PCa cells in order to test the potential of the simultaneous treatment with PSMA-617 and <sup>177</sup>Lu-PSMA-617 for the translation in a clinical trial.
REF00267	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Drug uptake dose	31 cpm/&micro;g	cpm/&micro;g	.	.	.	.	Prostate carcinoma	LNCaP cell	.	.	30 min	"<sup>177</sup>Lu-PSMA-617 0.44 nM, 2 MBq/4 ml/dish; PSMA-617 (10 nM)"	.	"Both <sup>177</sup>Lu-PSMA-617 and its non-radioactive precursor, PSMA-617, bind to the PSMA on the cell membrane. Therefore, PSMA-617 could compete with the <sup>177</sup>Lu-PSMA-617- binding to LNCaP cells and, consequently may reduce its cytotoxic effects. However, PSMA-617 concentrations up to 100 nM did not impair the <sup>177</sup>Lu-PSMA-617 uptake into the LNCaP cells (n = 9). Effects of PSMA-617 (10, 50 and 100 nM) (solid columns) on the uptake of <sup>177</sup>Lu-PSMA-617 into LNCaP cells. Empty column, cells treated with vehicle. Results are expressed as the means &plusmn; SD. No significant differences among the groups were found (one-way ANOVA)."	Our results indicate that PSMA-617 inhibits proliferation of PCa cells and potentiates the cell death-promoting effects of <sup>177</sup>Lu-PSMA-617. These findings require further confirmation in vitro and in vivo experiments to study the exact molecular mechanisms associated with the growth-inhibitory effects of PSMA-617 observed in PCa cells in order to test the potential of the simultaneous treatment with PSMA-617 and <sup>177</sup>Lu-PSMA-617 for the translation in a clinical trial.
REF00271	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	7.5 months	months	.	.	.	55 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	At least 2 cycles	"7,400 MBq/cycles"	.	"Progression occurred in all patients, with a median time to the event of 7.5 mo (95% CI, 4.7-10.3 mo). An %IDred value above the median in both LNM and BM was associated with shorter survival. Moreover, higher %ID within the LNM correlated with longer survival. The kinetics of <sup>177</sup>Lu-PSMA-617 within the organ metastasis had no prognostic implications."	"The <sup>177</sup>Lu-PSMA-617 kinetics in LNM and BM appear to be prognostic of treatment response, as well as of survival. In particular, OS appears to be linked with the kinetics parameters of BM, in keeping with the concept that BM is the most threatening pathogenic mechanism of mCRPC. This information, which should be confirmed by prospective trials, is readily obtainable from posttherapy scans and could be used to prognosticate treatment outcomes and design studies aimed to investigate the potential of PET-based prediction, as well as the possibility of patient-adapted therapeutic protocols of RLT."
REF00271	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	16.3 months	months	.	.	.	55 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	At least 2 cycles	"7,400 MBq/cycles"	.	"Forty-three patients died of disease. OS from the RLT start was 16.3 mo (95% CI, 11.1-21.6). %IDred in BM predicted OS, but neither LNM nor BM %ID was associated with OS."	"The <sup>177</sup>Lu-PSMA-617 kinetics in LNM and BM appear to be prognostic of treatment response, as well as of survival. In particular, OS appears to be linked with the kinetics parameters of BM, in keeping with the concept that BM is the most threatening pathogenic mechanism of mCRPC. This information, which should be confirmed by prospective trials, is readily obtainable from posttherapy scans and could be used to prognosticate treatment outcomes and design studies aimed to investigate the potential of PET-based prediction, as well as the possibility of patient-adapted therapeutic protocols of RLT."
REF00273	PDC_00027	Pancreatic neuroendocrine tumor	QGP-1 cells athymic nude male mice xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor volume	800 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	Pancreatic somatostatinoma	QGP-1 cell	.	.	15 days	30 MBq/mouse	.	"Using an identical 10-day CI-994 pretreatment model, the mice that received a single intravenous administration of 30 MBq of <sup>177</sup>Lu-DOTATATE after CI-994 pretreatment demonstrated a significant reduction in tumor growth compared with the control group (P < 0.0001) and to the group receiving standard therapy, that is, 30 MBq <sup>177</sup>Lu-DOTATATE alone (P = 0.0028). This was confirmed 11 and 15 days after <sup>177</sup>Lu-DOTATATE injections. And, the effects of combination therapy were additive, that is, there was no interaction effect between CI-994 and <sup>177</sup>Lu-DOTATATE. The clear difference in tumor growth after 5 days of <sup>177</sup>Lu-DOTATATE therapy between the two CI-994-pretreated groups signaled a strong response to <sup>177</sup>Lu-DOTATATE. Tumor growth was not slowed in the <sup>177</sup>Lu-DOTATATE-only treatment group, potentially due to SSTR2 deficiency. Notably, the combined CI-994 and <sup>177</sup>Lu-DOTATATE treatment appeared well-tolerated, with limited toxicity as evidenced by some changes in mouse body weight as observed in other studies, with no visible toxicity signs at the time of euthanasia. Tumors of mice treated with combined CI-994 and <sup>177</sup>Lu-DOTATATE were significantly smaller compared with tumors of mice treated <sup>177</sup>Lu-DOTATATE alone. Furthermore, Pan H3 staining revealed increased open chromatin (red foci, Pan H3) in tumors treated with CI-994 in comparison to control tumors. And increased DNA damage (green foci, &gamma;H2AX) was observed in these CI-994-pretreated tumors compared with control after <sup>177</sup>Lu-DOTATATE therapy. This increase in DNA damage was found to be significant (P < 0.001)."	"In conclusion, our preclinical data demonstrate that pretreatment with the HDACi CI-994 improves <sup>177</sup>Lu-DOTATATE therapy, compared with PRRT alone in models of SSTR2-deficient NETs. Our study forms the basis for a clinical trial testing the therapeutic efficacy of HDACi CI-994 pretreatment in combination with <sup>177</sup>Lu-DOTATATE therapy in patients with high-grade, SSTR2-negative metastatic PNETs."
REF00273	PDC_00027	Pancreatic neuroendocrine tumor	QGP-1 cells athymic nude male mice xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	35.84%	%	.	.	.	.	Pancreatic somatostatinoma	QGP-1 cell	.	.	15 days	30 MBq/mouse	.	"Using an identical 10-day CI-994 pretreatment model, the mice that received a single intravenous administration of 30 MBq of <sup>177</sup>Lu-DOTATATE after CI-994 pretreatment demonstrated a significant reduction in tumor growth compared with the control group (P < 0.0001) and to the group receiving standard therapy, that is, 30 MBq <sup>177</sup>Lu-DOTATATE alone (P = 0.0028). This was confirmed 11 and 15 days after <sup>177</sup>Lu-DOTATATE injections. And, the effects of combination therapy were additive, that is, there was no interaction effect between CI-994 and <sup>177</sup>Lu-DOTATATE. The clear difference in tumor growth after 5 days of <sup>177</sup>Lu-DOTATATE therapy between the two CI-994-pretreated groups signaled a strong response to <sup>177</sup>Lu-DOTATATE. Tumor growth was not slowed in the <sup>177</sup>Lu-DOTATATE-only treatment group, potentially due to SSTR2 deficiency. Notably, the combined CI-994 and <sup>177</sup>Lu-DOTATATE treatment appeared well-tolerated, with limited toxicity as evidenced by some changes in mouse body weight as observed in other studies, with no visible toxicity signs at the time of euthanasia. Tumors of mice treated with combined CI-994 and <sup>177</sup>Lu-DOTATATE were significantly smaller compared with tumors of mice treated <sup>177</sup>Lu-DOTATATE alone. Furthermore, Pan H3 staining revealed increased open chromatin (red foci, Pan H3) in tumors treated with CI-994 in comparison to control tumors. And increased DNA damage (green foci, &gamma;H2AX) was observed in these CI-994-pretreated tumors compared with control after <sup>177</sup>Lu-DOTATATE therapy. This increase in DNA damage was found to be significant (P < 0.001)."	"In conclusion, our preclinical data demonstrate that pretreatment with the HDACi CI-994 improves <sup>177</sup>Lu-DOTATATE therapy, compared with PRRT alone in models of SSTR2-deficient NETs. Our study forms the basis for a clinical trial testing the therapeutic efficacy of HDACi CI-994 pretreatment in combination with <sup>177</sup>Lu-DOTATATE therapy in patients with high-grade, SSTR2-negative metastatic PNETs."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	45.00%	%	.	.	.	145 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-4 cycles	2-8 GBq/cycle	.	"The first major multi-center retrospective study on <sup>177</sup>Lu-PSMA-617 was published by Rahbar et al., reporting 145 patients with mCRPC who progressed after second-line systemic therapies. The overall response rate in terms of serum PSA decline >50% was seen in 45% of patients after all <sup>177</sup>Lu-PSMA-617 cycles. On imaging, 21 (45%) patients and 13 (28%) patients had PR and SD, respectively. There was grade 3-4 toxicity in 18 patients (13%), which included severe anemia, thrombocytopenia, and leukopenia. They found elevated alkaline phosphatase and visceral metastases as negative predictors of response to <sup>177</sup>Lu-PSMA-617. A major drawback of this study was the variable cycles and doses of <sup>177</sup>Lu-PSMA-617 given to patients"	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	60%	%	.	.	.	145 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-4 cycles	2-8 GBq/cycle	.	"The first major multi-center retrospective study on <sup>177</sup>Lu-PSMA-617 was published by Rahbar et al., reporting 145 patients with mCRPC who progressed after second-line systemic therapies. The overall response rate in terms of serum PSA decline >50% was seen in 45% of patients after all <sup>177</sup>Lu-PSMA-617 cycles. On imaging, 21 (45%) patients and 13 (28%) patients had PR and SD, respectively. There was grade 3-4 toxicity in 18 patients (13%), which included severe anemia, thrombocytopenia, and leukopenia. They found elevated alkaline phosphatase and visceral metastases as negative predictors of response to <sup>177</sup>Lu-PSMA-617. A major drawback of this study was the variable cycles and doses of <sup>177</sup>Lu-PSMA-617 given to patients"	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	41.50%	%	.	.	.	416 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	3 cycles	.	.	"Since initial retrospective studies had a limited number of patients and a heterogeneous population, the WARMTH (World Association of Radiopharmaceutical and Molecular Therapy) planned a multi-center retrospective study to evaluate response rate, OS, and the impact of prior therapies on OS in more than 300 mCRPC patients treated with <sup>177</sup>Lu-PSMA-617. The study included 416 mCRPC patients who received a total of 1493 cycles of <sup>177</sup>Lu-PSMA-617, with a median of 3 cycles per patient. Post-<sup>177</sup>Lu-PSMA-617, serum PSA decline was seen in 282 (71.8%) patients, of whom 163 (41.5%) showed a serum PSA decline of &ge;50%, whereas 111 patients (28.2%) showed an increase in serum PSA levels. A median OS of 11.1 months (95% CI 9.7-12.5 months) was observed. Prior chemotherapy, the presence of bone and liver metastases, and poor ECOG status were significant adverse prognosticators for survival in both univariate and multivariate analyses. No imaging response evaluation and no determination of PFS after <sup>177</sup>Lu-PSMA-617 were major limitations for this study."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	71.80%	%	.	.	.	416 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	3 cycles	.	.	"Since initial retrospective studies had a limited number of patients and a heterogeneous population, the WARMTH (World Association of Radiopharmaceutical and Molecular Therapy) planned a multi-center retrospective study to evaluate response rate, OS, and the impact of prior therapies on OS in more than 300 mCRPC patients treated with <sup>177</sup>Lu-PSMA-617. The study included 416 mCRPC patients who received a total of 1493 cycles of <sup>177</sup>Lu-PSMA-617, with a median of 3 cycles per patient. Post-<sup>177</sup>Lu-PSMA-617, serum PSA decline was seen in 282 (71.8%) patients, of whom 163 (41.5%) showed a serum PSA decline of &ge;50%, whereas 111 patients (28.2%) showed an increase in serum PSA levels. A median OS of 11.1 months (95% CI 9.7-12.5 months) was observed. Prior chemotherapy, the presence of bone and liver metastases, and poor ECOG status were significant adverse prognosticators for survival in both univariate and multivariate analyses. No imaging response evaluation and no determination of PFS after <sup>177</sup>Lu-PSMA-617 were major limitations for this study."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	52.50%	%	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2-5 cycles	4.44-5.55 GBq/cycle	.	"Suman et al. evaluated the efficacy of <sup>177</sup>Lu-PSMA-617 in heavily pre-treated mCRPC patients. A total of 40 mCRPC patients who received at least 2 cycles of <sup>177</sup>Lu-PSMA-617 were included in this study. Twenty-one (52.5%) patients were responders (CR, PR, and SD) and 19 (47.5%) patients were non-responders (PD) on both symptomatic and biochemical scales. As per PET response criteria in solid tumor (PERCIST) criteria, 16 patients (43%) and 21 patients (57%) were responders and non-responders, respectively, on 68Ga-PSMA-11 PET/CT imaging. Metastatic nodal lesions responded better compared to liver and bony lesions. The median OS of 12 months and the median PFS of 7 months were registered without any grade 3/4 toxicity. The authors concluded that <sup>177</sup>Lu-PSMA-617 controlled disease with good symptomatic and biochemical response rates without any high-grade clinical toxicity."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA decline	75-90%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	3 cycles	3.8-6.7 GBq/cycle	.	"Yordanova et al., evaluated the response rate and clinical toxicity of re-challenge <sup>177</sup>Lu-PSMA-617 in progressive prostatic cancer patients who previously benefited from this therapy. In this retrospective study, a total of 30 patients were re-treated with a median of 3 (range 1-6) cycles of <sup>177</sup>Lu-PSMA-617. They found that 75-90% of patients demonstrated favorable serum PSA responses following re-challenge cycles, with a median OS of 12 months after the first re-challenge cycle and without any life-threatening grade-4 adverse event. The authors concluded that the majority of patients benefited from re-challenging <sup>177</sup>Lu-PSMA-617 with a longer OS in biochemically responsive patients. At present, data on re-challenge <sup>177</sup>Lu-PSMA-617 is limited and requires a prospective randomized trial before a definitive conclusion."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274; REF00063	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	46.00%	%	.	.	.	"175 metastatic castration-resistant prostate cancer (mCRPC) patient were included in this meta-analysis. 46% of patients had greater than 50% PSA decline after <sup>177</sup>Lu-PSMA RLT, and a higher proportion (75%) had any PSA decline after therapy."	.	.	.	.	.	3.7-8.7 GBq/cycle	.	"Yadav et al. provided a meta-analysis of <sup>177</sup>Lu-PSMA-PRLT for treating mCRPC patients. They analyzed 16 articles (13 articles used <sup>177</sup>Lu-PSMA-617, 2 articles used <sup>177</sup>Lu-PSMA-I&T, and 1 article used both radioligands). The authors showed >50% PSA decline after <sup>177</sup>Lu-PSMA-PRLT in 46% of patients. Anatomical imaging response as per the RECIST criteria was reported by eight studies, with a proportion of 37.2% of patients had PR, SD in 38.3% of patients and PD in 24.5% of patients, whereas molecular imaging response as per the PERCIST criteria demonstrated PR in 74 patients (44.3%), SD in 39 patients (23.4%), and PD in 54 patients (32.3%). Common clinical toxicities were grades 1-2, which included anemia (23%), leukopenia (14.2%), thrombocytopenia (15%), nephrotoxicity (9.5%), and xerostomia (14.5%). The authors observed significant heterogeneity in several studies while analyzing this meta-analysis. They concluded that <sup>177</sup>Lu-PSMA-PRLT is a promising treatment modality in mCRPC patients who showed PD after standard care treatments."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	50.00%	%	.	.	.	2346 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	6 GBq/cycle	.	Von Eyben et al. published a review and meta-analysis on <sup>177</sup>Lu-PSMA-PRLT with the inclusion of 2346 patients. They found a median OS of 16 months after PRLT and longer survival in asymptomatic patients and those with only lymph node metastatic disease as compared to symptomatic patients and those with extensive disease. They also demonstrated &ge;50% PSA decline in 50% of patients with longer survival as compared to those with <50% PSA decline. Hematologic toxicity was observed in approximately 10% of the patients with anemia of grade 3 as the most severe adverse effect of <sup>177</sup>Lu-PSMA-PRLT. The authors mentioned that the intensified schedule of <sup>177</sup>Lu-PSMA-PRLT (increased dose activity up to 9 GBq per cycle with a shortened time interval between cycles) increases the survival and efficacy of PRLT without increasing hematological toxicity.	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274; REF00033	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	44.00%	%	.	.	.	"Twelve studies including 669 metastatic castration-resistant prostate cancer patients reported <sup>177</sup>Lu-PSMA radioligand therapy(RLT). <sup>177</sup>Lu-PSMA RLT caused a best decline of PSA &ge;50% twice as often as the third-line treatment (mean frequency 44% versus 22%, p=0.0002, t-test)."	.	.	.	.	.	.	.	"A systematic review on the comparison of <sup>177</sup>Lu-PSMA-PRLT with third-line treatments such as abiraterone, enzalutamide, and cabazitaxel was published by Von Eyben et al. A significant difference of PSA response was seen between the two groups (a PSA decline of &ge;50% in 44% of patients in Lu-PSMA-PRLT group versus only 22% of patients in third-line treatment group). The authors mentioned that, despite variations in doses and number of cycles, <sup>177</sup>Lu-PSMA-PRLT group showed a favorable response rate as compared to the third-line treatment group, and they also mentioned more side effects and discontinuation of third-line treatment as compared to <sup>177</sup>Lu-PSMA- PRLT group."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	57.00%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6weeks interval.	.	.	.	.	1-4 cycles	4.4-8.7 GBq/cycle	.	"In 2018, a phase II trial on <sup>177</sup>Lu-PSMA-617 (LuPSMA trial) was published by Hofman et al. In this study, they included a total of 30 mCRPC patients who showed PD on standard therapies and received 1-4 cycles with 7.5 GBq of <sup>177</sup>Lu-PSMA-617 (range: 4.4-8.7 GBq). They found >50% PSA decline in 17 patients (57%) and an objective response rate of 40%, 37%, and 37% of patients on 68Ga PSMA-11, FDG-PET/CT, and bone imaging, respectively. The median PFS was 7.6 months, and the median OS was 13.5 months after <sup>177</sup>Lu-PSMA-617. Improvement in pain level was noted in 27 patients (90%), which significantly contributed to a better quality of life. <sup>177</sup>Lu-PSMA-617 was well tolerated with minimal side effects. Commonly seen side effects were grade 1 dryness of mouth (87%), grade 1-2 transient nausea (50%) and fatigue (50%). Uncommonly seen side effects included grade 3-4 thrombocytopenia (13%), grade 3 anemia (13%), and neutropenia (7%). This was the first prospective single-arm, single-center, phase II study on the use of <sup>177</sup>Lu-PSMA-617 in mCRPC patients."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	45.50%	%	.	.	.	90 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-7 cycles	3.7-8 GBq/cycle	.	"A favorable response rate (PSA and objective response) and safe profile of <sup>177</sup>Lu-PSMA-617 were demonstrated in this study, leading to greater use of Lu-PSMA-PRLT in clinical practices. Similarly, Yadav et al. reported favorable outcomes of <sup>177</sup>Lu-PSMA-617 in a prospective, single-arm, single-center study in 90 mCRPC patients."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	45%	%	.	.	.	145 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-4 cycles	2-8 GBq/cycle	PET/CT assay	"The first major multi-center retrospective study on <sup>177</sup>Lu-PSMA-617 was published by Rahbar et al., reporting 145 patients with mCRPC who progressed after second-line systemic therapies. The overall response rate in terms of serum PSA decline >50% was seen in 45% of patients after all <sup>177</sup>Lu-PSMA-617 cycles. On imaging, 21 (45%) patients and 13 (28%) patients had PR and SD, respectively. There was grade 3-4 toxicity in 18 patients (13%), which included severe anemia, thrombocytopenia, and leukopenia. They found elevated alkaline phosphatase and visceral metastases as negative predictors of response to <sup>177</sup>Lu-PSMA-617. A major drawback of this study was the variable cycles and doses of <sup>177</sup>Lu-PSMA-617 given to patients"	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	28%	%	.	.	.	145 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-4 cycles	2-8 GBq/cycle	PET/CT assay	"The first major multi-center retrospective study on <sup>177</sup>Lu-PSMA-617 was published by Rahbar et al., reporting 145 patients with mCRPC who progressed after second-line systemic therapies. The overall response rate in terms of serum PSA decline >50% was seen in 45% of patients after all <sup>177</sup>Lu-PSMA-617 cycles. On imaging, 21 (45%) patients and 13 (28%) patients had PR and SD, respectively. There was grade 3-4 toxicity in 18 patients (13%), which included severe anemia, thrombocytopenia, and leukopenia. They found elevated alkaline phosphatase and visceral metastases as negative predictors of response to <sup>177</sup>Lu-PSMA-617. A major drawback of this study was the variable cycles and doses of <sup>177</sup>Lu-PSMA-617 given to patients"	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	40%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	3 cycles	3.8-6.7 GBq/cycle	PET/CT assay	"Yordanova et al., evaluated the response rate and clinical toxicity of re-challenge <sup>177</sup>Lu-PSMA-617 in progressive prostatic cancer patients who previously benefited from this therapy. In this retrospective study, a total of 30 patients were re-treated with a median of 3 (range 1-6) cycles of <sup>177</sup>Lu-PSMA-617. They found that 75-90% of patients demonstrated favorable serum PSA responses following re-challenge cycles, with a median OS of 12 months after the first re-challenge cycle and without any life-threatening grade-4 adverse event. The authors concluded that the majority of patients benefited from re-challenging <sup>177</sup>Lu-PSMA-617 with a longer OS in biochemically responsive patients. At present, data on re-challenge <sup>177</sup>Lu-PSMA-617 is limited and requires a prospective randomized trial before a definitive conclusion."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274; REF00063	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	37.20%	%	.	.	.	"175 metastatic castration-resistant prostate cancer (mCRPC) patient were included in this meta-analysis. 65 (37.2%) patients experienced partial remission, 67 had stable disease (38.3%), and 43 (24.5%) had progressive disease."	.	.	.	.	.	3.7-8.7 GBq/cycle	PET/CT assay	"Yadav et al. provided a meta-analysis of <sup>177</sup>Lu-PSMA-PRLT for treating mCRPC patients. They analyzed 16 articles (13 articles used <sup>177</sup>Lu-PSMA-617, 2 articles used <sup>177</sup>Lu-PSMA-I&T, and 1 article used both radioligands). The authors showed >50% PSA decline after <sup>177</sup>Lu-PSMA-PRLT in 46% of patients. Anatomical imaging response as per the RECIST criteria was reported by eight studies, with a proportion of 37.2% of patients had PR, SD in 38.3% of patients and PD in 24.5% of patients, whereas molecular imaging response as per the PERCIST criteria demonstrated PR in 74 patients (44.3%), SD in 39 patients (23.4%), and PD in 54 patients (32.3%). Common clinical toxicities were grades 1-2, which included anemia (23%), leukopenia (14.2%), thrombocytopenia (15%), nephrotoxicity (9.5%), and xerostomia (14.5%). The authors observed significant heterogeneity in several studies while analyzing this meta-analysis. They concluded that <sup>177</sup>Lu-PSMA-PRLT is a promising treatment modality in mCRPC patients who showed PD after standard care treatments."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274; REF00063	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	38.30%	%	.	.	.	"175 metastatic castration-resistant prostate cancer (mCRPC) patient were included in this meta-analysis. 65 (37.2%) patients experienced partial remission, 67 had stable disease (38.3%), and 43 (24.5%) had progressive disease."	.	.	.	.	.	3.7-8.7 GBq/cycle	PET/CT assay	"Yadav et al. provided a meta-analysis of <sup>177</sup>Lu-PSMA-PRLT for treating mCRPC patients. They analyzed 16 articles (13 articles used <sup>177</sup>Lu-PSMA-617, 2 articles used <sup>177</sup>Lu-PSMA-I&T, and 1 article used both radioligands). The authors showed >50% PSA decline after <sup>177</sup>Lu-PSMA-PRLT in 46% of patients. Anatomical imaging response as per the RECIST criteria was reported by eight studies, with a proportion of 37.2% of patients had PR, SD in 38.3% of patients and PD in 24.5% of patients, whereas molecular imaging response as per the PERCIST criteria demonstrated PR in 74 patients (44.3%), SD in 39 patients (23.4%), and PD in 54 patients (32.3%). Common clinical toxicities were grades 1-2, which included anemia (23%), leukopenia (14.2%), thrombocytopenia (15%), nephrotoxicity (9.5%), and xerostomia (14.5%). The authors observed significant heterogeneity in several studies while analyzing this meta-analysis. They concluded that <sup>177</sup>Lu-PSMA-PRLT is a promising treatment modality in mCRPC patients who showed PD after standard care treatments."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274; REF00063	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	24.50%	%	.	.	.	"175 metastatic castration-resistant prostate cancer (mCRPC) patient were included in this meta-analysis. 65 (37.2%) patients experienced partial remission, 67 had stable disease (38.3%), and 43 (24.5%) had progressive disease."	.	.	.	.	.	3.7-8.7 GBq/cycle	PET/CT assay	"Yadav et al. provided a meta-analysis of <sup>177</sup>Lu-PSMA-PRLT for treating mCRPC patients. They analyzed 16 articles (13 articles used <sup>177</sup>Lu-PSMA-617, 2 articles used <sup>177</sup>Lu-PSMA-I&T, and 1 article used both radioligands). The authors showed >50% PSA decline after <sup>177</sup>Lu-PSMA-PRLT in 46% of patients. Anatomical imaging response as per the RECIST criteria was reported by eight studies, with a proportion of 37.2% of patients had PR, SD in 38.3% of patients and PD in 24.5% of patients, whereas molecular imaging response as per the PERCIST criteria demonstrated PR in 74 patients (44.3%), SD in 39 patients (23.4%), and PD in 54 patients (32.3%). Common clinical toxicities were grades 1-2, which included anemia (23%), leukopenia (14.2%), thrombocytopenia (15%), nephrotoxicity (9.5%), and xerostomia (14.5%). The authors observed significant heterogeneity in several studies while analyzing this meta-analysis. They concluded that <sup>177</sup>Lu-PSMA-PRLT is a promising treatment modality in mCRPC patients who showed PD after standard care treatments."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274; REF00033	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	29%	%	.	.	.	"Twelve studies including 669 metastatic castration-resistant prostate cancer patients reported <sup>177</sup>Lu-PSMA radioligand therapy(RLT). Of evaluable articles, a median of 29% (IQR 8-36%) of the patients had objective remission."	.	.	.	.	.	.	PET/CT assay	"A systematic review on the comparison of <sup>177</sup>Lu-PSMA-PRLT with third-line treatments such as abiraterone, enzalutamide, and cabazitaxel was published by Von Eyben et al. A significant difference of PSA response was seen between the two groups (a PSA decline of &ge;50% in 44% of patients in Lu-PSMA-PRLT group versus only 22% of patients in third-line treatment group). The authors mentioned that, despite variations in doses and number of cycles, <sup>177</sup>Lu-PSMA-PRLT group showed a favorable response rate as compared to the third-line treatment group, and they also mentioned more side effects and discontinuation of third-line treatment as compared to <sup>177</sup>Lu-PSMA- PRLT group."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	40%	%	.	.	.	30 patients with metastatic castration-resistant prostate cancer who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6weeks interval.	.	.	.	.	1-4 cycles	4.4-8.7 GBq/cycle	PET/CT assay	"In 2018, a phase II trial on <sup>177</sup>Lu-PSMA-617 (LuPSMA trial) was published by Hofman et al. In this study, they included a total of 30 mCRPC patients who showed PD on standard therapies and received 1-4 cycles with 7.5 GBq of <sup>177</sup>Lu-PSMA-617 (range: 4.4-8.7 GBq). They found >50% PSA decline in 17 patients (57%) and an objective response rate of 40%, 37%, and 37% of patients on 68Ga PSMA-11, FDG-PET/CT, and bone imaging, respectively. The median PFS was 7.6 months, and the median OS was 13.5 months after <sup>177</sup>Lu-PSMA-617. Improvement in pain level was noted in 27 patients (90%), which significantly contributed to a better quality of life. <sup>177</sup>Lu-PSMA-617 was well tolerated with minimal side effects. Commonly seen side effects were grade 1 dryness of mouth (87%), grade 1-2 transient nausea (50%) and fatigue (50%). Uncommonly seen side effects included grade 3-4 thrombocytopenia (13%), grade 3 anemia (13%), and neutropenia (7%). This was the first prospective single-arm, single-center, phase II study on the use of <sup>177</sup>Lu-PSMA-617 in mCRPC patients."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	23%	%	.	.	.	90 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-7 cycles	3.7-8 GBq/cycle	PET/CT assay	"A favorable response rate (PSA and objective response) and safe profile of <sup>177</sup>Lu-PSMA-617 were demonstrated in this study, leading to greater use of Lu-PSMA-PRLT in clinical practices. Similarly, Yadav et al. reported favorable outcomes of <sup>177</sup>Lu-PSMA-617 in a prospective, single-arm, single-center study in 90 mCRPC patients."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	54%	%	.	.	.	90 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-7 cycles	3.7-8 GBq/cycle	PET/CT assay	"A favorable response rate (PSA and objective response) and safe profile of <sup>177</sup>Lu-PSMA-617 were demonstrated in this study, leading to greater use of Lu-PSMA-PRLT in clinical practices. Similarly, Yadav et al. reported favorable outcomes of <sup>177</sup>Lu-PSMA-617 in a prospective, single-arm, single-center study in 90 mCRPC patients."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	23%	%	.	.	.	90 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-7 cycles	3.7-8 GBq/cycle	PET/CT assay	"A favorable response rate (PSA and objective response) and safe profile of <sup>177</sup>Lu-PSMA-617 were demonstrated in this study, leading to greater use of Lu-PSMA-PRLT in clinical practices. Similarly, Yadav et al. reported favorable outcomes of <sup>177</sup>Lu-PSMA-617 in a prospective, single-arm, single-center study in 90 mCRPC patients."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	7 months	months	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2-5 cycles	4.44-5.55 GBq/cycle	.	"Suman et al. evaluated the efficacy of <sup>177</sup>Lu-PSMA-617 in heavily pre-treated mCRPC patients. A total of 40 mCRPC patients who received at least 2 cycles of <sup>177</sup>Lu-PSMA-617 were included in this study. Twenty-one (52.5%) patients were responders (CR, PR, and SD) and 19 (47.5%) patients were non-responders (PD) on both symptomatic and biochemical scales. As per PET response criteria in solid tumor (PERCIST) criteria, 16 patients (43%) and 21 patients (57%) were responders and non-responders, respectively, on 68Ga-PSMA-11 PET/CT imaging. Metastatic nodal lesions responded better compared to liver and bony lesions. The median OS of 12 months and the median PFS of 7 months were registered without any grade 3/4 toxicity. The authors concluded that <sup>177</sup>Lu-PSMA-617 controlled disease with good symptomatic and biochemical response rates without any high-grade clinical toxicity."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	2.8 months	months	.	.	.	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	3 cycles	3.8-6.7 GBq/cycle	.	"Yordanova et al., evaluated the response rate and clinical toxicity of re-challenge <sup>177</sup>Lu-PSMA-617 in progressive prostatic cancer patients who previously benefited from this therapy. In this retrospective study, a total of 30 patients were re-treated with a median of 3 (range 1-6) cycles of <sup>177</sup>Lu-PSMA-617. They found that 75-90% of patients demonstrated favorable serum PSA responses following re-challenge cycles, with a median OS of 12 months after the first re-challenge cycle and without any life-threatening grade-4 adverse event. The authors concluded that the majority of patients benefited from re-challenging <sup>177</sup>Lu-PSMA-617 with a longer OS in biochemically responsive patients. At present, data on re-challenge <sup>177</sup>Lu-PSMA-617 is limited and requires a prospective randomized trial before a definitive conclusion."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274; REF00063	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	11 months	months	.	.	.	"175 metastatic castration-resistant prostate cancer (mCRPC) patient were included in this meta-analysis. Median PFS was delineated in five studies and was 11 months (IQR, 7.6-13.7 months)."	.	.	.	.	.	3.7-8.7 GBq/cycle	.	"Yadav et al. provided a meta-analysis of <sup>177</sup>Lu-PSMA-PRLT for treating mCRPC patients. They analyzed 16 articles (13 articles used <sup>177</sup>Lu-PSMA-617, 2 articles used <sup>177</sup>Lu-PSMA-I&T, and 1 article used both radioligands). The authors showed >50% PSA decline after <sup>177</sup>Lu-PSMA-PRLT in 46% of patients. Anatomical imaging response as per the RECIST criteria was reported by eight studies, with a proportion of 37.2% of patients had PR, SD in 38.3% of patients and PD in 24.5% of patients, whereas molecular imaging response as per the PERCIST criteria demonstrated PR in 74 patients (44.3%), SD in 39 patients (23.4%), and PD in 54 patients (32.3%). Common clinical toxicities were grades 1-2, which included anemia (23%), leukopenia (14.2%), thrombocytopenia (15%), nephrotoxicity (9.5%), and xerostomia (14.5%). The authors observed significant heterogeneity in several studies while analyzing this meta-analysis. They concluded that <sup>177</sup>Lu-PSMA-PRLT is a promising treatment modality in mCRPC patients who showed PD after standard care treatments."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	7.6 months	months	.	.	.	30 patients with metastatic castration-resistant prostate cancer who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6weeks interval.	.	.	.	.	1-4 cycles	4.4-8.7 GBq/cycle	.	"In 2018, a phase II trial on <sup>177</sup>Lu-PSMA-617 (LuPSMA trial) was published by Hofman et al. In this study, they included a total of 30 mCRPC patients who showed PD on standard therapies and received 1-4 cycles with 7.5 GBq of <sup>177</sup>Lu-PSMA-617 (range: 4.4-8.7 GBq). They found >50% PSA decline in 17 patients (57%) and an objective response rate of 40%, 37%, and 37% of patients on 68Ga PSMA-11, FDG-PET/CT, and bone imaging, respectively. The median PFS was 7.6 months, and the median OS was 13.5 months after <sup>177</sup>Lu-PSMA-617. Improvement in pain level was noted in 27 patients (90%), which significantly contributed to a better quality of life. <sup>177</sup>Lu-PSMA-617 was well tolerated with minimal side effects. Commonly seen side effects were grade 1 dryness of mouth (87%), grade 1-2 transient nausea (50%) and fatigue (50%). Uncommonly seen side effects included grade 3-4 thrombocytopenia (13%), grade 3 anemia (13%), and neutropenia (7%). This was the first prospective single-arm, single-center, phase II study on the use of <sup>177</sup>Lu-PSMA-617 in mCRPC patients."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	11.8 months	months	.	.	.	90 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-7 cycles	3.7-8 GBq/cycle	.	"A favorable response rate (PSA and objective response) and safe profile of <sup>177</sup>Lu-PSMA-617 were demonstrated in this study, leading to greater use of Lu-PSMA-PRLT in clinical practices. Similarly, Yadav et al. reported favorable outcomes of <sup>177</sup>Lu-PSMA-617 in a prospective, single-arm, single-center study in 90 mCRPC patients."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	11.1 months	months	.	.	.	416 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	3 cycles	.	.	"Since initial retrospective studies had a limited number of patients and a heterogeneous population, the WARMTH (World Association of Radiopharmaceutical and Molecular Therapy) planned a multi-center retrospective study to evaluate response rate, OS, and the impact of prior therapies on OS in more than 300 mCRPC patients treated with <sup>177</sup>Lu-PSMA-617. The study included 416 mCRPC patients who received a total of 1493 cycles of <sup>177</sup>Lu-PSMA-617, with a median of 3 cycles per patient. Post-<sup>177</sup>Lu-PSMA-617, serum PSA decline was seen in 282 (71.8%) patients, of whom 163 (41.5%) showed a serum PSA decline of &ge;50%, whereas 111 patients (28.2%) showed an increase in serum PSA levels. A median OS of 11.1 months (95% CI 9.7-12.5 months) was observed. Prior chemotherapy, the presence of bone and liver metastases, and poor ECOG status were significant adverse prognosticators for survival in both univariate and multivariate analyses. No imaging response evaluation and no determination of PFS after <sup>177</sup>Lu-PSMA-617 were major limitations for this study."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	12 months	months	.	.	.	40 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	2-5 cycles	4.44-5.55 GBq/cycle	.	"Suman et al. evaluated the efficacy of <sup>177</sup>Lu-PSMA-617 in heavily pre-treated mCRPC patients. A total of 40 mCRPC patients who received at least 2 cycles of <sup>177</sup>Lu-PSMA-617 were included in this study. Twenty-one (52.5%) patients were responders (CR, PR, and SD) and 19 (47.5%) patients were non-responders (PD) on both symptomatic and biochemical scales. As per PET response criteria in solid tumor (PERCIST) criteria, 16 patients (43%) and 21 patients (57%) were responders and non-responders, respectively, on 68Ga-PSMA-11 PET/CT imaging. Metastatic nodal lesions responded better compared to liver and bony lesions. The median OS of 12 months and the median PFS of 7 months were registered without any grade 3/4 toxicity. The authors concluded that <sup>177</sup>Lu-PSMA-617 controlled disease with good symptomatic and biochemical response rates without any high-grade clinical toxicity."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	12 months	months	.	.	.	30 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	3 cycles	3.8-6.7 GBq/cycle	.	"Yordanova et al., evaluated the response rate and clinical toxicity of re-challenge <sup>177</sup>Lu-PSMA-617 in progressive prostatic cancer patients who previously benefited from this therapy. In this retrospective study, a total of 30 patients were re-treated with a median of 3 (range 1-6) cycles of <sup>177</sup>Lu-PSMA-617. They found that 75-90% of patients demonstrated favorable serum PSA responses following re-challenge cycles, with a median OS of 12 months after the first re-challenge cycle and without any life-threatening grade-4 adverse event. The authors concluded that the majority of patients benefited from re-challenging <sup>177</sup>Lu-PSMA-617 with a longer OS in biochemically responsive patients. At present, data on re-challenge <sup>177</sup>Lu-PSMA-617 is limited and requires a prospective randomized trial before a definitive conclusion."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274; REF00063	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	13.7 months	months	.	.	.	175 metastatic castration-resistant prostate cancer (mCRPC) patient were included in this meta-analysis. Median OS was 13.7 months.	.	.	.	.	.	3.7-8.7 GBq/cycle	.	"Yadav et al. provided a meta-analysis of <sup>177</sup>Lu-PSMA-PRLT for treating mCRPC patients. They analyzed 16 articles (13 articles used <sup>177</sup>Lu-PSMA-617, 2 articles used <sup>177</sup>Lu-PSMA-I&T, and 1 article used both radioligands). The authors showed >50% PSA decline after <sup>177</sup>Lu-PSMA-PRLT in 46% of patients. Anatomical imaging response as per the RECIST criteria was reported by eight studies, with a proportion of 37.2% of patients had PR, SD in 38.3% of patients and PD in 24.5% of patients, whereas molecular imaging response as per the PERCIST criteria demonstrated PR in 74 patients (44.3%), SD in 39 patients (23.4%), and PD in 54 patients (32.3%). Common clinical toxicities were grades 1-2, which included anemia (23%), leukopenia (14.2%), thrombocytopenia (15%), nephrotoxicity (9.5%), and xerostomia (14.5%). The authors observed significant heterogeneity in several studies while analyzing this meta-analysis. They concluded that <sup>177</sup>Lu-PSMA-PRLT is a promising treatment modality in mCRPC patients who showed PD after standard care treatments."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	16 months	months	.	.	.	2346 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	6 GBq/cycle	.	Von Eyben et al. published a review and meta-analysis on <sup>177</sup>Lu-PSMA-PRLT with the inclusion of 2346 patients. They found a median OS of 16 months after PRLT and longer survival in asymptomatic patients and those with only lymph node metastatic disease as compared to symptomatic patients and those with extensive disease. They also demonstrated &ge;50% PSA decline in 50% of patients with longer survival as compared to those with <50% PSA decline. Hematologic toxicity was observed in approximately 10% of the patients with anemia of grade 3 as the most severe adverse effect of <sup>177</sup>Lu-PSMA-PRLT. The authors mentioned that the intensified schedule of <sup>177</sup>Lu-PSMA-PRLT (increased dose activity up to 9 GBq per cycle with a shortened time interval between cycles) increases the survival and efficacy of PRLT without increasing hematological toxicity.	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274; REF00033	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	14 months	months	.	.	.	"Twelve studies including 669 metastatic castration-resistant prostate cancer patients reported <sup>177</sup>Lu-PSMA radioligand therapy(RLT). In evaluable articles, the patients had a median overall survival of 14 months."	.	.	.	.	.	.	.	"A systematic review on the comparison of <sup>177</sup>Lu-PSMA-PRLT with third-line treatments such as abiraterone, enzalutamide, and cabazitaxel was published by Von Eyben et al. A significant difference of PSA response was seen between the two groups (a PSA decline of &ge;50% in 44% of patients in Lu-PSMA-PRLT group versus only 22% of patients in third-line treatment group). The authors mentioned that, despite variations in doses and number of cycles, <sup>177</sup>Lu-PSMA-PRLT group showed a favorable response rate as compared to the third-line treatment group, and they also mentioned more side effects and discontinuation of third-line treatment as compared to <sup>177</sup>Lu-PSMA- PRLT group."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	13.5 months	months	.	.	.	30 patients with metastatic castration-resistant prostate cancer who underwent 4 cycles of mean 7.5 GBq Lu-PSMA 617 at 6weeks interval.	.	.	.	.	1-4 cycles	4.4-8.7 GBq/cycle	.	"In 2018, a phase II trial on <sup>177</sup>Lu-PSMA-617 (LuPSMA trial) was published by Hofman et al. In this study, they included a total of 30 mCRPC patients who showed PD on standard therapies and received 1-4 cycles with 7.5 GBq of <sup>177</sup>Lu-PSMA-617 (range: 4.4-8.7 GBq). They found >50% PSA decline in 17 patients (57%) and an objective response rate of 40%, 37%, and 37% of patients on 68Ga PSMA-11, FDG-PET/CT, and bone imaging, respectively. The median PFS was 7.6 months, and the median OS was 13.5 months after <sup>177</sup>Lu-PSMA-617. Improvement in pain level was noted in 27 patients (90%), which significantly contributed to a better quality of life. <sup>177</sup>Lu-PSMA-617 was well tolerated with minimal side effects. Commonly seen side effects were grade 1 dryness of mouth (87%), grade 1-2 transient nausea (50%) and fatigue (50%). Uncommonly seen side effects included grade 3-4 thrombocytopenia (13%), grade 3 anemia (13%), and neutropenia (7%). This was the first prospective single-arm, single-center, phase II study on the use of <sup>177</sup>Lu-PSMA-617 in mCRPC patients."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00274	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	14 months	months	.	.	.	90 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	1-7 cycles	3.7-8 GBq/cycle	.	"A favorable response rate (PSA and objective response) and safe profile of <sup>177</sup>Lu-PSMA-617 were demonstrated in this study, leading to greater use of Lu-PSMA-PRLT in clinical practices. Similarly, Yadav et al. reported favorable outcomes of <sup>177</sup>Lu-PSMA-617 in a prospective, single-arm, single-center study in 90 mCRPC patients."	"The PSMA molecule acts as a target for theranostics in detecting and treating prostatic lesions. This ultimately promotes the concept of precision and personalized medicine. Several published articles showed favorable outcomes of Lu-PSMA-PRLT in mCRPC patients, which quickly translated into routine clinical practices with real effectiveness, a low toxicity profile, and documentation of the risk-benefit of PRLT. Nevertheless, many questions related to PRLT remain unresolved such as the sequencing of PRLT with ARTA or taxane-based chemotherapy, re-challenge therapy, combined therapy, alpha therapy in mCRPC patients, and early treatment of PRLT in mHNPC patients. To solve these questions, several clinical trials are currently under way, and the results of these trials will be helpful in deciding treatment strategies for prostate cancer patients."
REF00277	PDC_00007	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	4.50%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	5 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00008	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	3.50%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	5 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	3.50%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	5 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00007	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	8%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	15 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00008	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	5.50%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	15 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	5.50%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	15 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00007	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	14%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	30 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00008	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	7.50%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	30 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	6%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	30 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00007	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	17%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	60 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00008	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	8%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	60 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	7%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	60 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00007	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	20%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	120 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00008	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	10%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	120 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00277	PDC_00029	Metastatic castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell uptake rate	9%	%	.	.	.	.	Prostate carcinoma	PC3-PIP PSMA-positive cell	.	.	120 min	37 kBq	Gamma counter assay	"As expected, the PSMA-targeting hetero-bivalent agents, [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2, displayed excellent cell uptake in PC3-PIP PSMA-positive cells. Furthermore, [<sup>177</sup>Lu]Lu-1 displayed a higher uptake (about 2 times higher, p < 0.05) as that of [<sup>177</sup>Lu]Lu-2. The higher uptake in PSMA-positive cells suggested that [<sup>177</sup>Lu]Lu-1 may more readily penetrate the cell membrane and may be more localized in the PSMA-positive tumor cells. The uptake was specifically inhibited by blocking study (in the presence of 1 uM cold PSMA-617). Both agents did not show any significant cell uptakes in PSMA-negative cells (PC3 cells). Cell uptake kinetics of [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 showed very rapid uptakes in PC3-PIP PSMA-positive cells (5, 15, 30, 60, and 120 min, respectively). As a positive control, [<sup>177</sup>Lu]Lu-PSMA-617 also showed excellent cell uptake under a similar condition. It is noted that [<sup>177</sup>Lu]Lu-2 showed a very similar uptake kinetics as that of [<sup>177</sup>Lu]Lu-PSMA-617, while [<sup>177</sup>Lu]Lu-1 displayed a significantly higher and faster uptake. Apparently, a small change in the chemical structure of the location of the bisphosphonate group between [<sup>177</sup>Lu]Lu-1 and [<sup>177</sup>Lu]Lu-2 may have contributed to this observation. No obvious reason could be contributed to the superior cell uptake of [<sup>177</sup>Lu]Lu-1. This distinctive difference in in vitro cell uptake may also be responsible for variations of PSMA-positive tumor uptakes in vivo."	"Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [<sup>177</sup>Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) and [<sup>177</sup>Lu]Lu-P17-081 ([<sup>177</sup>Lu]Lu-2) were prepared. In vivo biodistribution studies of [<sup>177</sup>Lu]Lu-PSMA-617, [<sup>177</sup>Lu]Lu-1, and [<sup>177</sup>Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [<sup>177</sup>Lu]Lu-P17-079 ([<sup>177</sup>Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	11%	%	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 (iqr: 3-6) cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"Four (21%) patients showed no response (PD) to the <sup>177</sup>Lu-PSMA-RLT cycles after the first treatment break, and in two patients (11%), progression after the initial disease stabilization (SD) under subsequent cycles led to treatment discontinuation. Two patients (11%) completed the intended six cycles with a stable disease. In the remaining 11/19 (84%) patients, resuming <sup>177</sup>Lu-PSMA-RLT resulted in a repeated PR. Altogether, 14/19 (74%) patients died by the time of this analysis. The median PFS was 27 (95% CI: 23-31) months and the OS was 45 (95% CI: 28-62) months."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	11%	%	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 (iqr: 3-6) cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"Four (21%) patients showed no response (PD) to the <sup>177</sup>Lu-PSMA-RLT cycles after the first treatment break, and in two patients (11%), progression after the initial disease stabilization (SD) under subsequent cycles led to treatment discontinuation. Two patients (11%) completed the intended six cycles with a stable disease. In the remaining 11/19 (84%) patients, resuming <sup>177</sup>Lu-PSMA-RLT resulted in a repeated PR. Altogether, 14/19 (74%) patients died by the time of this analysis. The median PFS was 27 (95% CI: 23-31) months and the OS was 45 (95% CI: 28-62) months."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	84%	%	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 (iqr: 3-6) cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"Four (21%) patients showed no response (PD) to the <sup>177</sup>Lu-PSMA-RLT cycles after the first treatment break, and in two patients (11%), progression after the initial disease stabilization (SD) under subsequent cycles led to treatment discontinuation. Two patients (11%) completed the intended six cycles with a stable disease. In the remaining 11/19 (84%) patients, resuming <sup>177</sup>Lu-PSMA-RLT resulted in a repeated PR. Altogether, 14/19 (74%) patients died by the time of this analysis. The median PFS was 27 (95% CI: 23-31) months and the OS was 45 (95% CI: 28-62) months."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	27 months	months	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 (iqr: 3-6) cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"Four (21%) patients showed no response (PD) to the <sup>177</sup>Lu-PSMA-RLT cycles after the first treatment break, and in two patients (11%), progression after the initial disease stabilization (SD) under subsequent cycles led to treatment discontinuation. Two patients (11%) completed the intended six cycles with a stable disease. In the remaining 11/19 (84%) patients, resuming <sup>177</sup>Lu-PSMA-RLT resulted in a repeated PR. Altogether, 14/19 (74%) patients died by the time of this analysis. The median PFS was 27 (95% CI: 23-31) months and the OS was 45 (95% CI: 28-62) months."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	45 months	months	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 (iqr: 3-6) cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"Four (21%) patients showed no response (PD) to the <sup>177</sup>Lu-PSMA-RLT cycles after the first treatment break, and in two patients (11%), progression after the initial disease stabilization (SD) under subsequent cycles led to treatment discontinuation. Two patients (11%) completed the intended six cycles with a stable disease. In the remaining 11/19 (84%) patients, resuming <sup>177</sup>Lu-PSMA-RLT resulted in a repeated PR. Altogether, 14/19 (74%) patients died by the time of this analysis. The median PFS was 27 (95% CI: 23-31) months and the OS was 45 (95% CI: 28-62) months."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 anemia	84%	%	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 (iqr: 3-6) cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"No grade &ge; 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 &plusmn; 18.0 mL/min/1.73 m2 at baseline to 73.4 &plusmn; 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 &plusmn; 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 &plusmn; 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 &plusmn; 7 vs. 30 &plusmn; 10 GBq, p = 0.036). No grade &ge; 3 hematological toxicity was observed during intermittent <sup>177</sup>Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent <sup>177</sup>Lu-PSMA-RLT. Mean Hb declined from 12.7 &plusmn; 1.4 to 12.0 &plusmn; 1.6 g/dL (p = 0.021), WBC declined from 7.4 &plusmn; 2.8 109/L to 5.9 &plusmn; 1.6 109/L (p = 0.005), and PLT declined from 233 &plusmn; 76 109/L to 218 &plusmn; 71 109/L (p = 0.047). Significant xerostomia was not detected during <sup>177</sup>Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 leukopenia	16%	%	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 (iqr: 3-6) cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"No grade &ge; 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 &plusmn; 18.0 mL/min/1.73 m2 at baseline to 73.4 &plusmn; 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 &plusmn; 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 &plusmn; 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 &plusmn; 7 vs. 30 &plusmn; 10 GBq, p = 0.036). No grade &ge; 3 hematological toxicity was observed during intermittent <sup>177</sup>Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent <sup>177</sup>Lu-PSMA-RLT. Mean Hb declined from 12.7 &plusmn; 1.4 to 12.0 &plusmn; 1.6 g/dL (p = 0.021), WBC declined from 7.4 &plusmn; 2.8 109/L to 5.9 &plusmn; 1.6 109/L (p = 0.005), and PLT declined from 233 &plusmn; 76 109/L to 218 &plusmn; 71 109/L (p = 0.047). Significant xerostomia was not detected during <sup>177</sup>Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 thrombocytopenia	32%	%	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 (iqr: 3-6) cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"No grade &ge; 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 &plusmn; 18.0 mL/min/1.73 m2 at baseline to 73.4 &plusmn; 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 &plusmn; 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 &plusmn; 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 &plusmn; 7 vs. 30 &plusmn; 10 GBq, p = 0.036). No grade &ge; 3 hematological toxicity was observed during intermittent <sup>177</sup>Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent <sup>177</sup>Lu-PSMA-RLT. Mean Hb declined from 12.7 &plusmn; 1.4 to 12.0 &plusmn; 1.6 g/dL (p = 0.021), WBC declined from 7.4 &plusmn; 2.8 109/L to 5.9 &plusmn; 1.6 109/L (p = 0.005), and PLT declined from 233 &plusmn; 76 109/L to 218 &plusmn; 71 109/L (p = 0.047). Significant xerostomia was not detected during <sup>177</sup>Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 eGFR *	16%	%	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 (iqr: 3-6) cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"No grade &ge; 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 &plusmn; 18.0 mL/min/1.73 m2 at baseline to 73.4 &plusmn; 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 &plusmn; 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 &plusmn; 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 &plusmn; 7 vs. 30 &plusmn; 10 GBq, p = 0.036). No grade &ge; 3 hematological toxicity was observed during intermittent <sup>177</sup>Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent <sup>177</sup>Lu-PSMA-RLT. Mean Hb declined from 12.7 &plusmn; 1.4 to 12.0 &plusmn; 1.6 g/dL (p = 0.021), WBC declined from 7.4 &plusmn; 2.8 109/L to 5.9 &plusmn; 1.6 109/L (p = 0.005), and PLT declined from 233 &plusmn; 76 109/L to 218 &plusmn; 71 109/L (p = 0.047). Significant xerostomia was not detected during <sup>177</sup>Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 xerostomia	5%	%	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	5 (iqr: 3-6) cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"No grade &ge; 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 &plusmn; 18.0 mL/min/1.73 m2 at baseline to 73.4 &plusmn; 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 &plusmn; 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 &plusmn; 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 &plusmn; 7 vs. 30 &plusmn; 10 GBq, p = 0.036). No grade &ge; 3 hematological toxicity was observed during intermittent <sup>177</sup>Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent <sup>177</sup>Lu-PSMA-RLT. Mean Hb declined from 12.7 &plusmn; 1.4 to 12.0 &plusmn; 1.6 g/dL (p = 0.021), WBC declined from 7.4 &plusmn; 2.8 109/L to 5.9 &plusmn; 1.6 109/L (p = 0.005), and PLT declined from 233 &plusmn; 76 109/L to 218 &plusmn; 71 109/L (p = 0.047). Significant xerostomia was not detected during <sup>177</sup>Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 anemia	68%	%	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	45 &plusmn; 21 months after all cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"No grade &ge; 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 &plusmn; 18.0 mL/min/1.73 m2 at baseline to 73.4 &plusmn; 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 &plusmn; 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 &plusmn; 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 &plusmn; 7 vs. 30 &plusmn; 10 GBq, p = 0.036). No grade &ge; 3 hematological toxicity was observed during intermittent <sup>177</sup>Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent <sup>177</sup>Lu-PSMA-RLT. Mean Hb declined from 12.7 &plusmn; 1.4 to 12.0 &plusmn; 1.6 g/dL (p = 0.021), WBC declined from 7.4 &plusmn; 2.8 109/L to 5.9 &plusmn; 1.6 109/L (p = 0.005), and PLT declined from 233 &plusmn; 76 109/L to 218 &plusmn; 71 109/L (p = 0.047). Significant xerostomia was not detected during <sup>177</sup>Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 leukopenia	5%	%	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	45 &plusmn; 21 months after all cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"No grade &ge; 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 &plusmn; 18.0 mL/min/1.73 m2 at baseline to 73.4 &plusmn; 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 &plusmn; 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 &plusmn; 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 &plusmn; 7 vs. 30 &plusmn; 10 GBq, p = 0.036). No grade &ge; 3 hematological toxicity was observed during intermittent <sup>177</sup>Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent <sup>177</sup>Lu-PSMA-RLT. Mean Hb declined from 12.7 &plusmn; 1.4 to 12.0 &plusmn; 1.6 g/dL (p = 0.021), WBC declined from 7.4 &plusmn; 2.8 109/L to 5.9 &plusmn; 1.6 109/L (p = 0.005), and PLT declined from 233 &plusmn; 76 109/L to 218 &plusmn; 71 109/L (p = 0.047). Significant xerostomia was not detected during <sup>177</sup>Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 thrombocytopenia	15%	%	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	45 &plusmn; 21 months after all cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"No grade &ge; 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 &plusmn; 18.0 mL/min/1.73 m2 at baseline to 73.4 &plusmn; 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 &plusmn; 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 &plusmn; 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 &plusmn; 7 vs. 30 &plusmn; 10 GBq, p = 0.036). No grade &ge; 3 hematological toxicity was observed during intermittent <sup>177</sup>Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent <sup>177</sup>Lu-PSMA-RLT. Mean Hb declined from 12.7 &plusmn; 1.4 to 12.0 &plusmn; 1.6 g/dL (p = 0.021), WBC declined from 7.4 &plusmn; 2.8 109/L to 5.9 &plusmn; 1.6 109/L (p = 0.005), and PLT declined from 233 &plusmn; 76 109/L to 218 &plusmn; 71 109/L (p = 0.047). Significant xerostomia was not detected during <sup>177</sup>Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 eGFR *	5%	%	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	45 &plusmn; 21 months after all cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"No grade &ge; 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 &plusmn; 18.0 mL/min/1.73 m2 at baseline to 73.4 &plusmn; 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 &plusmn; 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 &plusmn; 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 &plusmn; 7 vs. 30 &plusmn; 10 GBq, p = 0.036). No grade &ge; 3 hematological toxicity was observed during intermittent <sup>177</sup>Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent <sup>177</sup>Lu-PSMA-RLT. Mean Hb declined from 12.7 &plusmn; 1.4 to 12.0 &plusmn; 1.6 g/dL (p = 0.021), WBC declined from 7.4 &plusmn; 2.8 109/L to 5.9 &plusmn; 1.6 109/L (p = 0.005), and PLT declined from 233 &plusmn; 76 109/L to 218 &plusmn; 71 109/L (p = 0.047). Significant xerostomia was not detected during <sup>177</sup>Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00280	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Grade 1/2 xerostomia	5%	%	.	.	.	19 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	45 &plusmn; 21 months after all cycles	A cumulative activity of 32 &plusmn; 11 GBq	68Ga-PSMA-11 PET/CT assay	"No grade &ge; 3 nephrotoxicity was observed but mean eGFR-levels declined from 80.6 &plusmn; 18.0 mL/min/1.73 m2 at baseline to 73.4 &plusmn; 15.6 mL/min/1.73 m2 (p = 0.055) at the last follow-up. The mean absorbed renal dose was 0.53 &plusmn; 0.21 Gy/GBq, with significant absorbed doses from the first cycle onward, resulting in a cumulative absorbed renal dose of 16.7 &plusmn; 8.3 Gy. A significant correlation, however, between the cumulative renal absorbed dose and administered activity (rs = 0.576, p = 0.010) could be observed. Concordantly, in 3/19 (16%) patients with an absorbed renal dose >28 Gy, the administered activity was significantly higher than in patients with <28 Gy of absorbed renal dose (44 &plusmn; 7 vs. 30 &plusmn; 10 GBq, p = 0.036). No grade &ge; 3 hematological toxicity was observed during intermittent <sup>177</sup>Lu-PSMA-RLT or follow-up. Nevertheless, Hb, WBC, and PLT showed an absolute decline throughout the course of intermittent <sup>177</sup>Lu-PSMA-RLT. Mean Hb declined from 12.7 &plusmn; 1.4 to 12.0 &plusmn; 1.6 g/dL (p = 0.021), WBC declined from 7.4 &plusmn; 2.8 109/L to 5.9 &plusmn; 1.6 109/L (p = 0.005), and PLT declined from 233 &plusmn; 76 109/L to 218 &plusmn; 71 109/L (p = 0.047). Significant xerostomia was not detected during <sup>177</sup>Lu-PSMA-RLT and the follow-up period; one patient developed mild to moderate xerostomia after three treatment cycles, which was not reversible during follow-up."	"Intermittent <sup>177</sup>Lu-PSMA-617 radioligand therapy in early responders with oligometastatic castration-resistant prostate cancer seems to not compromise survival outcome, despite long treatment-free intervals. The safety profile remained favorable, warranting further investigation of the concept of intermittent treatment in selected patients with a longer life-expectancy."
REF00281	PDC_00029	Metastatic castration-resistant prostate cancer	A 70-year-old man with history of prostate cancer.	Identified from the Human Clinical Data	High Expreesion	PSA decline	90%	%	.	.	.	.	.	.	.	.	3 cycles and an interval of 6-8 weeks	5.5 GBq/cycle	.	"A 70-year-old man with history of prostate cancer was referred to our department for 68Ga-PSMA PET/CT. He had been diagnosed with prostate adenocarcinoma 12 years earlier, with a Gleason score of 5 + 5 = 10. He had a complaint of skin nodules on the pubis and the left lower extremity swelling that had appeared for a few months. Physical examination revealed multiple indurated, erythematous, and infiltrating papulonodular lesions with the largest 3.5 2.3 cm over the pubis (A). The PSA level was 755 ng/mL. Increased 68Ga-PSMA uptakes were seen to correspond to most of the cutaneous lesions on pubis, with a mean SUVmax of 25. In addition, there were multiple pelvic and retroperitoneal lymph nodes showing increased PSMA uptake (SUVmax, 17) highly suggestive of lymph node metastasis (B) and increased PSMA uptakes in the cutaneous and subcutaneous tissues and edema in the left lower extremity (C). Given the patient history, skin nodules showing increased 68Ga-PSMA uptake were suspected to be metastatic lesions from prostate carcinoma as well. Histological evaluation and immunohistochemical staining with PSA, prostate-specific acid phosphatase (PSAP), cytokeratin 20 (CK20), and CDX2 were consistent with metastatic prostate adenocarcinoma to cutaneous tissue. <sup>177</sup>Lu-PSMA radioligand treatment was planned because the lesions showed increased PSMA uptakes. After a total of 3 cycles <sup>177</sup>Lu-PSMA-617 (with a mean activity of 5.5 GBq per cycle and an interval of 6-8 weeks), it was observed that the existing all skin lesions disappeared. Also 68Ga-PSMA PET/CT scan revealed that all lesions showing increased PSMA uptake disappeared (D). The PSA level has dropped to 75 ng/mL."	"Although distant cutaneous metastasis is an uncommon presentation of prostate cancer, it remains an important diagnostic consideration as an advanced disease and a poor prognosis. Herein we present a rare case of prostate cancer patient whose multiple cutaneous metastases were treated with <sup>177</sup>Lu-PSMA-617 radioligand treatment. To our knowledge, it is the first report in which a complete response was seen with 68Ga-PSMA PET/CT scan after <sup>177</sup>Lu-PSMA-617 radioligand treatment."
REF00285	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	30.00%	%	.	.	.	61 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Median 4 (iqr: 2-6) cycles	Median 800 (IQR: 470-1150) mCi	.	"Mean follow-up time was 53.2&plusmn;24 months. While there were 61 patients at the baseline, 46 (75%) patients were able to complete the fourth cycle, and 18 (30%) patients were able to complete the eighth cycle. Median 4 (IQR: 2-6) cycles and 800 (IQR: 470-1150) mCi <sup>177</sup>Lu-PSMA-617 were applied. During the <sup>177</sup>Lu-PSMA-617 therapy period, androgen receptor signaling inhibitor was continued in 8 (13%) patients and chemotherapy was continued in 3 (5%) patients. According to the PCWG3 PSA response patterns, 18 (30%) patients had fitted into pattern 1 (PSA reduction of 50% or more from baseline and sustained), 12 (20%) patients into pattern 2 (PSA decrease of more than 50% followed by a modest rise), and 31 (51%) patients into pattern 3 (PSA progression of more than 25%). No significant difference was found between PSA patterns according to baseline inflammation indices (P values for NLR, dNLR, MLR, PLR, SII, PIV were.298,.105,.137,.774,.727,.944, respectively)."	"In conclusion, the current study was the first to demonstrate that pretreatment NLR, MLR, PLR and SII are powerful independent prognostic indices predicting survival in patients with mCRPC receiving <sup>177</sup>Lu-PSMA-617 therapy. A large-scale prospective study is warranted to confirm the preliminary results obtained in this study."
REF00285	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	20.00%	%	.	.	.	61 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Median 4 (iqr: 2-6) cycles	Median 800 (IQR: 470-1150) mCi	.	"Mean follow-up time was 53.2&plusmn;24 months. While there were 61 patients at the baseline, 46 (75%) patients were able to complete the fourth cycle, and 18 (30%) patients were able to complete the eighth cycle. Median 4 (IQR: 2-6) cycles and 800 (IQR: 470-1150) mCi <sup>177</sup>Lu-PSMA-617 were applied. During the <sup>177</sup>Lu-PSMA-617 therapy period, androgen receptor signaling inhibitor was continued in 8 (13%) patients and chemotherapy was continued in 3 (5%) patients. According to the PCWG3 PSA response patterns, 18 (30%) patients had fitted into pattern 1 (PSA reduction of 50% or more from baseline and sustained), 12 (20%) patients into pattern 2 (PSA decrease of more than 50% followed by a modest rise), and 31 (51%) patients into pattern 3 (PSA progression of more than 25%). No significant difference was found between PSA patterns according to baseline inflammation indices (P values for NLR, dNLR, MLR, PLR, SII, PIV were.298,.105,.137,.774,.727,.944, respectively)."	"In conclusion, the current study was the first to demonstrate that pretreatment NLR, MLR, PLR and SII are powerful independent prognostic indices predicting survival in patients with mCRPC receiving <sup>177</sup>Lu-PSMA-617 therapy. A large-scale prospective study is warranted to confirm the preliminary results obtained in this study."
REF00285	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	PSA progression rate	51%	%	.	.	.	61 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	Median 4 (iqr: 2-6) cycles	Median 800 (IQR: 470-1150) mCi	.	"Mean follow-up time was 53.2&plusmn;24 months. While there were 61 patients at the baseline, 46 (75%) patients were able to complete the fourth cycle, and 18 (30%) patients were able to complete the eighth cycle. Median 4 (IQR: 2-6) cycles and 800 (IQR: 470-1150) mCi <sup>177</sup>Lu-PSMA-617 were applied. During the <sup>177</sup>Lu-PSMA-617 therapy period, androgen receptor signaling inhibitor was continued in 8 (13%) patients and chemotherapy was continued in 3 (5%) patients. According to the PCWG3 PSA response patterns, 18 (30%) patients had fitted into pattern 1 (PSA reduction of 50% or more from baseline and sustained), 12 (20%) patients into pattern 2 (PSA decrease of more than 50% followed by a modest rise), and 31 (51%) patients into pattern 3 (PSA progression of more than 25%). No significant difference was found between PSA patterns according to baseline inflammation indices (P values for NLR, dNLR, MLR, PLR, SII, PIV were.298,.105,.137,.774,.727,.944, respectively)."	"In conclusion, the current study was the first to demonstrate that pretreatment NLR, MLR, PLR and SII are powerful independent prognostic indices predicting survival in patients with mCRPC receiving <sup>177</sup>Lu-PSMA-617 therapy. A large-scale prospective study is warranted to confirm the preliminary results obtained in this study."
REF00286	PDC_00027	Intracranial meningioma	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival at 6 months	50%	%	.	.	.	14 patients with intracranial meningioma.	.	.	.	.	Every eight weeks for four cycles	7.4 GBq (200 mCi) per cycles	68Ga-DOTATATE PET-MRI assay	"Fourteen patients (female = 11, male = 3) with progressive meningiomas (WHO 1 = 3, 2 = 10, 3 = 1) were enrolled. Median age was 63.1 (range 49.7-78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with <sup>177</sup>Lu-DOTATATE was well tolerated. Seven patients (50%) achieved PFS-6. Best radiographic response by modified Macdonald criteria was stable disease (SD) in all seven patients. A >25% reduction in 68Ga-DOTATATE uptake (PET) was observed in five meningiomas and two patients. In one lesion, this corresponded to >50% reduction in bidirectional tumor measurements (MRI)."	"Treatment with <sup>177</sup>Lu-DOTATATE was well tolerated. The predefined PFS-6 threshold was met in this interim analysis, thereby allowing this multicenter clinical trial to continue enrollment. 68Ga-DOTATATE PET may be a useful imaging biomarker to assess therapeutic outcome in patients with meningioma."
REF00297	PDC_00036	Pancreatic serotonin-producing neuroendocrine tumor	Dually implanted HCT116-WT/SSTR2 mice xenograft models.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Surviving fraction	80%	%	.	.	.	.	Pancreatic serotonin-producing neuroendocrine tumor	BON-1 cell	.	.	5 days	2 &mu;mol/L	Colony-forming assay	"TMZ is an alkylating agent that causes cell death through DNA-damaging mechanisms.?To determine whether MMC(TMZ)-TOC induces the same cytotoxic effects through a receptor-dependent process, we first studied its DNA-damaging properties in IMR-32 cells that endogenously express SSTR2. We performed an alkaline comet assay to evaluate the ability of our drug conjugate to produce single- and double-stranded DNA breaks. As shown in?Figure 3A,B, the targeted agent-induced DNA breaks that were similar to free TMZ, resulting in migrating DNA fragments (comet tail) from the nucleoid (comet head). The damaging effects of MMC(TMZ)-TOC were significantly reduced (P?< 0.0001) when cells were preincubated with blocking doses of the high-affinity SSTR2 antagonist JR11, indicating receptor-dependent cytotoxicity. Next, we used a colony formation assay to assess the long-term survival and reproductive capability of the cells after treatment with the PDC. We treated BON1 (receptor-negative) and BON1-SSTR2 (receptor-positive) cells with 2 mu;mol/L MMC(TMZ)-TOC or 10 mu;mol/L TMZ for 5 consecutive days, seeded the cells at a low-density number, and allowed them to grow and form colonies for 14 days. The clonogenic survival data showed that MMC(TMZ)-TOC produced cytotoxic effects in the receptor-positive BON1-SSTR2 cells (P?< 0.01) similar to clinically relevant doses of TMZ. Conversely, no cytotoxicity was observed in receptor-negative BON1 cells following treatment with the drug conjugate, further illustrating the receptor-dependent effects of the PDC."	"In this study, we hypothesized that the clinically utilized radiopharmaceutical 68Ga-DOTA-TOC could be converted to a radiolabeled peptide-drug conjugate (PDC) for selective delivery of TMZ to SSTR2-positive tumor cells. We used the intrinsic radiolabeling utility of the PDC to characterize receptor-binding properties, pharmacokinetics (PK), and tissue biodistribution in cells and animal studies. Receptor-targeted DNA-damaging properties and cytotoxic effects of the PDC were examined in different cell lines, and the effects of accumulated doses on MGMT content were evaluated in MGMT-positive cells."
REF00297	PDC_00036	Pancreatic serotonin-producing neuroendocrine tumor	Dually implanted HCT116-WT/SSTR2 mice xenograft models.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Surviving fraction	100%	%	.	.	.	.	Pancreatic serotonin-producing neuroendocrine tumor	BON-1 cell	.	.	5 days	2 &mu;mol/L	Colony-forming assay	"TMZ is an alkylating agent that causes cell death through DNA-damaging mechanisms.?To determine whether MMC(TMZ)-TOC induces the same cytotoxic effects through a receptor-dependent process, we first studied its DNA-damaging properties in IMR-32 cells that endogenously express SSTR2. We performed an alkaline comet assay to evaluate the ability of our drug conjugate to produce single- and double-stranded DNA breaks. As shown in?Figure 3A,B, the targeted agent-induced DNA breaks that were similar to free TMZ, resulting in migrating DNA fragments (comet tail) from the nucleoid (comet head). The damaging effects of MMC(TMZ)-TOC were significantly reduced (P?< 0.0001) when cells were preincubated with blocking doses of the high-affinity SSTR2 antagonist JR11, indicating receptor-dependent cytotoxicity. Next, we used a colony formation assay to assess the long-term survival and reproductive capability of the cells after treatment with the PDC. We treated BON1 (receptor-negative) and BON1-SSTR2 (receptor-positive) cells with 2 mu;mol/L MMC(TMZ)-TOC or 10 mu;mol/L TMZ for 5 consecutive days, seeded the cells at a low-density number, and allowed them to grow and form colonies for 14 days. The clonogenic survival data showed that MMC(TMZ)-TOC produced cytotoxic effects in the receptor-positive BON1-SSTR2 cells (P?< 0.01) similar to clinically relevant doses of TMZ. Conversely, no cytotoxicity was observed in receptor-negative BON1 cells following treatment with the drug conjugate, further illustrating the receptor-dependent effects of the PDC."	"In this study, we hypothesized that the clinically utilized radiopharmaceutical 68Ga-DOTA-TOC could be converted to a radiolabeled peptide-drug conjugate (PDC) for selective delivery of TMZ to SSTR2-positive tumor cells. We used the intrinsic radiolabeling utility of the PDC to characterize receptor-binding properties, pharmacokinetics (PK), and tissue biodistribution in cells and animal studies. Receptor-targeted DNA-damaging properties and cytotoxic effects of the PDC were examined in different cell lines, and the effects of accumulated doses on MGMT content were evaluated in MGMT-positive cells."
REF00297	PDC_00243	Neuroendocrine tumour	.	Revealed Based on the Cell Line Data	High Expreesion	Survival rate	100%	%	.	.	.	.	Pancreatic serotonin-producing neuroendocrine tumor	BON-1 cell	.	.	4-6 h/day for 5 consecutive days	2 &micro;mol/L	Colony-forming assay	"TMZ is an alkylating agent that causes cell death through DNA-damaging mechanisms. To determine whether MMC(TMZ)-TOC induces the same cytotoxic effects through a receptor-dependent process, we first studied its DNA-damaging properties in IMR-32 cells that endogenously express SSTR2. We performed an alkaline comet assay to evaluate the ability of our drug conjugate to produce single- and double-stranded DNA breaks. As shown in Figure 3A,B, the targeted agent-induced DNA breaks that were similar to free TMZ, resulting in migrating DNA fragments (comet tail) from the nucleoid (comet head). The damaging effects of MMC(TMZ)-TOC were significantly reduced (P < 0.0001) when cells were preincubated with blocking doses of the high-affinity SSTR2 antagonist JR11, indicating receptor-dependent cytotoxicity. Next, we used a colony formation assay to assess the long-term survival and reproductive capability of the cells after treatment with the PDC. We treated BON1 (receptor-negative) and BON1-SSTR2 (receptor-positive) cells with 2 umol/L MMC(TMZ)-TOC or 10 umol/L TMZ for 5 consecutive days, seeded the cells at a low-density number, and allowed them to grow and form colonies for 14 days. The clonogenic survival data showed that MMC(TMZ)-TOC produced cytotoxic effects in the receptor-positive BON1-SSTR2 cells (P < 0.01) similar to clinically relevant doses of TMZ. Conversely, no cytotoxicity was observed in receptor-negative BON1 cells following treatment with the drug conjugate, further illustrating the receptor-dependent effects of the PDC."	"In this study, we hypothesized that the clinically utilized radiopharmaceutical 68Ga-DOTA-TOC could be converted to a radiolabeled peptide-drug conjugate (PDC) for selective delivery of TMZ to SSTR2-positive tumor cells. We used the intrinsic radiolabeling utility of the PDC to characterize receptor-binding properties, pharmacokinetics (PK), and tissue biodistribution in cells and animal studies. Receptor-targeted DNA-damaging properties and cytotoxic effects of the PDC were examined in different cell lines, and the effects of accumulated doses on MGMT content were evaluated in MGMT-positive cells."
REF00297	PDC_00243	Neuroendocrine tumour	.	Revealed Based on the Cell Line Data	High Expreesion	Survival rate	80%	%	.	.	.	.	SSR2 positive neuroendocrine tumour	BON1-SSTR2 cell	.	.	4-6 h/day for 5 consecutive days	2 &micro;mol/L	Colony-forming assay	"TMZ is an alkylating agent that causes cell death through DNA-damaging mechanisms. To determine whether MMC(TMZ)-TOC induces the same cytotoxic effects through a receptor-dependent process, we first studied its DNA-damaging properties in IMR-32 cells that endogenously express SSTR2. We performed an alkaline comet assay to evaluate the ability of our drug conjugate to produce single- and double-stranded DNA breaks. As shown in Figure 3A,B, the targeted agent-induced DNA breaks that were similar to free TMZ, resulting in migrating DNA fragments (comet tail) from the nucleoid (comet head). The damaging effects of MMC(TMZ)-TOC were significantly reduced (P < 0.0001) when cells were preincubated with blocking doses of the high-affinity SSTR2 antagonist JR11, indicating receptor-dependent cytotoxicity. Next, we used a colony formation assay to assess the long-term survival and reproductive capability of the cells after treatment with the PDC. We treated BON1 (receptor-negative) and BON1-SSTR2 (receptor-positive) cells with 2 umol/L MMC(TMZ)-TOC or 10 umol/L TMZ for 5 consecutive days, seeded the cells at a low-density number, and allowed them to grow and form colonies for 14 days. The clonogenic survival data showed that MMC(TMZ)-TOC produced cytotoxic effects in the receptor-positive BON1-SSTR2 cells (P < 0.01) similar to clinically relevant doses of TMZ. Conversely, no cytotoxicity was observed in receptor-negative BON1 cells following treatment with the drug conjugate, further illustrating the receptor-dependent effects of the PDC."	"In this study, we hypothesized that the clinically utilized radiopharmaceutical 68Ga-DOTA-TOC could be converted to a radiolabeled peptide-drug conjugate (PDC) for selective delivery of TMZ to SSTR2-positive tumor cells. We used the intrinsic radiolabeling utility of the PDC to characterize receptor-binding properties, pharmacokinetics (PK), and tissue biodistribution in cells and animal studies. Receptor-targeted DNA-damaging properties and cytotoxic effects of the PDC were examined in different cell lines, and the effects of accumulated doses on MGMT content were evaluated in MGMT-positive cells."
REF00298	PDC_00029	Metastatic castration-resistant prostate cancer	A 79-year-old man with a history of metastatic prostate cancer.	Identified from the Human Clinical Data	High Expreesion	PSA decline	58.50%	%	.	.	.	.	.	.	.	.	.	.	.	"A 79-year-old man with a history of metastatic prostate cancer was initially treated with Eligard and switched to relugolix in 2021. The 2022 bone scan presented superscan and extensive osseous metastatic lesions; some had intense PSMA uptake on the initial PSMA PET scan without nodal or visceral metastatic lesions. We treated him with Pluvicto and relugolix. The intermediate PSMA scan demonstrated prominent bone marrow PSMA uptake. However, PSA decreased 58.5%. We hypothesized that the patient might have a bone flare. The final PSMA scan confirmed our hypothesis. Based on our knowledge, this is the first case of Pluvicto-induced bone flare."	.
REF00304	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	>50% PSA decline	61.00%	%	.	.	.	99 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%)."	"At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from <sup>177</sup>Lu-PSMA-617 radioligand therapy."
REF00304	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Anemia	33%	%	.	.	.	99 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%)."	"At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from <sup>177</sup>Lu-PSMA-617 radioligand therapy."
REF00304	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	21%	%	.	.	.	99 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	.	.	.	"Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%)."	"At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from <sup>177</sup>Lu-PSMA-617 radioligand therapy."
REF00307	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	8.7 months	months	.	.	Phase 3	551 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6 cycles	.	PSMA PET assay	"In the VISION trial, which enrolled patients with mCRPC who had received at least one line of ARPI treatment and one line of chemotherapy, <sup>177</sup>Lu-PSMA-617 improved imaging-based progression-free survival (PFS) by 60% (hazard ratio [HR] = 0.40; 95% confidence interval [CI] 0.29-0.57; p < 0.001) and OS by 38% (HR = 0.62; 95% CI 0.52-0.74; p < 0.001) vs. trial-permitted best standard of care (SOC). The median imaging-based PFS was 8.7 months and median OS was 15.3 months for the <sup>177</sup>Lu-PSMA-617 arm, vs. 3.4 months and 11.3 months, respectively, for the SOC arm."	"<sup>177</sup>Lu-PSMA-617 represents not just a new therapy but a new therapeutic class for the treatment of prostate cancer. As such, clinical pathways need to be developed and clinicians involved in the treatment of mCRPC must become familiar with these new processes in order to realize the benefits of RLT for their patients. While not all the suggestions included in this discussion are strictly evidence-based, it is the hope of the authors that this review of the evidence and associated expert opinions help practitioners translate these data into the current Canadian practice setting. Finally, as the therapeutic landscape for mCRPC continues to evolve, new treatments and emerging data will need to be considered when making treatment decisions."
REF00307	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	12 months	months	.	.	Phase 3	234 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6 cycles	.	PSMA PET assay	"In PSMAfore, which enrolled patients who were chemotherapy-nave, at the time of the second interim analysis median imaging-based PFS was 6.4 months longer in the <sup>177</sup>Lu-PSMA-617 arm vs. the ARPI change arm (HR = 0.43; 95% CI 0.33-0.54; p < 0.0001), while there was no significant difference in median OS, which was 19.25 vs. 19.71 months in the <sup>177</sup>Lu-PSMA-617 and ARPI change arms, respectively (HR = 1.18; 95% CI 0.83-1.64). It is important to note that a high crossover rate occurred, with 84.2% of patients who progressed in the ARPI change arm subsequently receiving <sup>177</sup>Lu-PSMA-617, thus likely diminishing the between-arm differences."	"<sup>177</sup>Lu-PSMA-617 represents not just a new therapy but a new therapeutic class for the treatment of prostate cancer. As such, clinical pathways need to be developed and clinicians involved in the treatment of mCRPC must become familiar with these new processes in order to realize the benefits of RLT for their patients. While not all the suggestions included in this discussion are strictly evidence-based, it is the hope of the authors that this review of the evidence and associated expert opinions help practitioners translate these data into the current Canadian practice setting. Finally, as the therapeutic landscape for mCRPC continues to evolve, new treatments and emerging data will need to be considered when making treatment decisions."
REF00307	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	15.3 months	months	.	.	Phase 3	551 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6 cycles	.	.	"In the VISION trial, which enrolled patients with mCRPC who had received at least one line of ARPI treatment and one line of chemotherapy, <sup>177</sup>Lu-PSMA-617 improved imaging-based progression-free survival (PFS) by 60% (hazard ratio [HR] = 0.40; 95% confidence interval [CI] 0.29-0.57; p < 0.001) and OS by 38% (HR = 0.62; 95% CI 0.52-0.74; p < 0.001) vs. trial-permitted best standard of care (SOC). The median imaging-based PFS was 8.7 months and median OS was 15.3 months for the <sup>177</sup>Lu-PSMA-617 arm, vs. 3.4 months and 11.3 months, respectively, for the SOC arm."	"<sup>177</sup>Lu-PSMA-617 represents not just a new therapy but a new therapeutic class for the treatment of prostate cancer. As such, clinical pathways need to be developed and clinicians involved in the treatment of mCRPC must become familiar with these new processes in order to realize the benefits of RLT for their patients. While not all the suggestions included in this discussion are strictly evidence-based, it is the hope of the authors that this review of the evidence and associated expert opinions help practitioners translate these data into the current Canadian practice setting. Finally, as the therapeutic landscape for mCRPC continues to evolve, new treatments and emerging data will need to be considered when making treatment decisions."
REF00307	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	19.2 months	months	.	.	Phase 3	234 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6 cycles	.	.	"In PSMAfore, which enrolled patients who were chemotherapy-nave, at the time of the second interim analysis median imaging-based PFS was 6.4 months longer in the <sup>177</sup>Lu-PSMA-617 arm vs. the ARPI change arm (HR = 0.43; 95% CI 0.33-0.54; p < 0.0001), while there was no significant difference in median OS, which was 19.25 vs. 19.71 months in the <sup>177</sup>Lu-PSMA-617 and ARPI change arms, respectively (HR = 1.18; 95% CI 0.83-1.64). It is important to note that a high crossover rate occurred, with 84.2% of patients who progressed in the ARPI change arm subsequently receiving <sup>177</sup>Lu-PSMA-617, thus likely diminishing the between-arm differences."	"<sup>177</sup>Lu-PSMA-617 represents not just a new therapy but a new therapeutic class for the treatment of prostate cancer. As such, clinical pathways need to be developed and clinicians involved in the treatment of mCRPC must become familiar with these new processes in order to realize the benefits of RLT for their patients. While not all the suggestions included in this discussion are strictly evidence-based, it is the hope of the authors that this review of the evidence and associated expert opinions help practitioners translate these data into the current Canadian practice setting. Finally, as the therapeutic landscape for mCRPC continues to evolve, new treatments and emerging data will need to be considered when making treatment decisions."
REF00307	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median health-related quality of life (HRQoL)	14.3 months	months	.	.	Phase 3	551 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6 cycles	.	.	"In the VISION trial, which enrolled patients with mCRPC who had received at least one line of ARPI treatment and one line of chemotherapy, <sup>177</sup>Lu-PSMA-617 improved imaging-based progression-free survival (PFS) by 60% (hazard ratio [HR] = 0.40; 95% confidence interval [CI] 0.29-0.57; p < 0.001) and OS by 38% (HR = 0.62; 95% CI 0.52-0.74; p < 0.001) vs. trial-permitted best standard of care (SOC). The median imaging-based PFS was 8.7 months and median OS was 15.3 months for the <sup>177</sup>Lu-PSMA-617 arm, vs. 3.4 months and 11.3 months, respectively, for the SOC arm."	"<sup>177</sup>Lu-PSMA-617 represents not just a new therapy but a new therapeutic class for the treatment of prostate cancer. As such, clinical pathways need to be developed and clinicians involved in the treatment of mCRPC must become familiar with these new processes in order to realize the benefits of RLT for their patients. While not all the suggestions included in this discussion are strictly evidence-based, it is the hope of the authors that this review of the evidence and associated expert opinions help practitioners translate these data into the current Canadian practice setting. Finally, as the therapeutic landscape for mCRPC continues to evolve, new treatments and emerging data will need to be considered when making treatment decisions."
REF00307	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median health-related quality of life (HRQoL)	7.5 months	months	.	.	Phase 3	234 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6 cycles	.	.	"In PSMAfore, which enrolled patients who were chemotherapy-nave, at the time of the second interim analysis median imaging-based PFS was 6.4 months longer in the <sup>177</sup>Lu-PSMA-617 arm vs. the ARPI change arm (HR = 0.43; 95% CI 0.33-0.54; p < 0.0001), while there was no significant difference in median OS, which was 19.25 vs. 19.71 months in the <sup>177</sup>Lu-PSMA-617 and ARPI change arms, respectively (HR = 1.18; 95% CI 0.83-1.64). It is important to note that a high crossover rate occurred, with 84.2% of patients who progressed in the ARPI change arm subsequently receiving <sup>177</sup>Lu-PSMA-617, thus likely diminishing the between-arm differences."	"<sup>177</sup>Lu-PSMA-617 represents not just a new therapy but a new therapeutic class for the treatment of prostate cancer. As such, clinical pathways need to be developed and clinicians involved in the treatment of mCRPC must become familiar with these new processes in order to realize the benefits of RLT for their patients. While not all the suggestions included in this discussion are strictly evidence-based, it is the hope of the authors that this review of the evidence and associated expert opinions help practitioners translate these data into the current Canadian practice setting. Finally, as the therapeutic landscape for mCRPC continues to evolve, new treatments and emerging data will need to be considered when making treatment decisions."
REF00307	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median time to pain progression	1 months	months	.	.	Phase 3	551 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6 cycles	.	.	"In the VISION trial, which enrolled patients with mCRPC who had received at least one line of ARPI treatment and one line of chemotherapy, <sup>177</sup>Lu-PSMA-617 improved imaging-based progression-free survival (PFS) by 60% (hazard ratio [HR] = 0.40; 95% confidence interval [CI] 0.29-0.57; p < 0.001) and OS by 38% (HR = 0.62; 95% CI 0.52-0.74; p < 0.001) vs. trial-permitted best standard of care (SOC). The median imaging-based PFS was 8.7 months and median OS was 15.3 months for the <sup>177</sup>Lu-PSMA-617 arm, vs. 3.4 months and 11.3 months, respectively, for the SOC arm."	"<sup>177</sup>Lu-PSMA-617 represents not just a new therapy but a new therapeutic class for the treatment of prostate cancer. As such, clinical pathways need to be developed and clinicians involved in the treatment of mCRPC must become familiar with these new processes in order to realize the benefits of RLT for their patients. While not all the suggestions included in this discussion are strictly evidence-based, it is the hope of the authors that this review of the evidence and associated expert opinions help practitioners translate these data into the current Canadian practice setting. Finally, as the therapeutic landscape for mCRPC continues to evolve, new treatments and emerging data will need to be considered when making treatment decisions."
REF00307	PDC_00029	Metastatic castration-resistant prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Median time to pain progression	5 months	months	.	.	Phase 3	234 patients with metastatic castration-resistant prostate cancer.	.	.	.	.	6 cycles	.	.	"In PSMAfore, which enrolled patients who were chemotherapy-nave, at the time of the second interim analysis median imaging-based PFS was 6.4 months longer in the <sup>177</sup>Lu-PSMA-617 arm vs. the ARPI change arm (HR = 0.43; 95% CI 0.33-0.54; p < 0.0001), while there was no significant difference in median OS, which was 19.25 vs. 19.71 months in the <sup>177</sup>Lu-PSMA-617 and ARPI change arms, respectively (HR = 1.18; 95% CI 0.83-1.64). It is important to note that a high crossover rate occurred, with 84.2% of patients who progressed in the ARPI change arm subsequently receiving <sup>177</sup>Lu-PSMA-617, thus likely diminishing the between-arm differences."	"<sup>177</sup>Lu-PSMA-617 represents not just a new therapy but a new therapeutic class for the treatment of prostate cancer. As such, clinical pathways need to be developed and clinicians involved in the treatment of mCRPC must become familiar with these new processes in order to realize the benefits of RLT for their patients. While not all the suggestions included in this discussion are strictly evidence-based, it is the hope of the authors that this review of the evidence and associated expert opinions help practitioners translate these data into the current Canadian practice setting. Finally, as the therapeutic landscape for mCRPC continues to evolve, new treatments and emerging data will need to be considered when making treatment decisions."
REF00311	PDC_00029	Metastatic castration-resistant prostate cancer	A 69-year-old man diagnosed with progressive bone metastatic castration-resistant prostate adenocarcinoma and concurrent alcoholic cirrhosis with multiple hepatocellular carcinoma (HCC).	Identified from the Human Clinical Data	High Expreesion	PSA decline rate	100%	%	.	.	.	.	.	.	.	.	.	.	.	"The -fetoprotein serum level increased from 248 to 578 kUI/L after the second treatment. We concluded that the prostatic disease exhibited a positive response to <sup>177</sup>Lu PSMA-617, evidenced by a significant decrease in PSA serum levels (from 1.26 ng/mL to undetectable levels after the second treatment). However, there was no observable effect on HCC nodules, prompting the patients readmission for chemoembolization. Notably, there is a high PSMA expression in various solid tumors neovessels, among others HCC."	.
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	25%	%	.	.	.	201 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	20%	%	.	.	.	330 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	13.90%	%	.	.	.	36 patients with paraganglioma.	.	.	.	.	4 cycles	.	.	"The efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating <sup>177</sup>Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after <sup>177</sup>LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of <sup>177</sup>Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	11.10%	%	.	.	.	18 patients with paraganglioma.	.	.	.	.	4 cycles	.	.	"The efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating <sup>177</sup>Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after <sup>177</sup>LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of <sup>177</sup>Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	16.70%	%	.	.	.	18 patients with paraganglioma.	.	.	.	.	4 cycles	.	.	"The efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating <sup>177</sup>Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after <sup>177</sup>LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of <sup>177</sup>Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00033	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	50%	%	.	.	.	9 patients with paraganglioma.	.	.	.	.	2-9 cycles	.	.	"Recently, a study in 9 patients of metastatic paragangliomas (7 patients received prior <sup>177</sup>Lu-DOTATATE and 3 out of 7 patients failed prior <sup>177</sup>Lu-DOTATATE) treated with 225Ac-DOTATATE ( particle based radiotherapy targeting SSTRs) and concomitant capecitabine showed a high partial response of 50% (compared to < 25% with particle targeted radiotherapies) and stable disease in 37.5% with a disease control rate of 87.5%, without any grade 3/4 hematotoxicity, nephrotoxicity, or hepatotoxicity."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	25%	%	.	.	.	201 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	20%	%	.	.	.	330 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	89.60%	%	.	.	.	179 patients with paraganglioma.	.	.	.	.	1-11 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	84%	%	.	.	.	201 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	90%	%	.	.	.	330 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	83%	%	.	.	.	149 patients with paraganglioma.	.	.	.	.	1-5 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	86.10%	%	.	.	.	36 patients with paraganglioma.	.	.	.	.	4 cycles	.	.	"The efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating <sup>177</sup>Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after <sup>177</sup>LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of <sup>177</sup>Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	100%	%	.	.	.	18 patients with paraganglioma.	.	.	.	.	4 cycles	.	.	"The efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating <sup>177</sup>Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after <sup>177</sup>LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of <sup>177</sup>Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	72.20%	%	.	.	.	18 patients with paraganglioma.	.	.	.	.	4 cycles	.	.	"The efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating <sup>177</sup>Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after <sup>177</sup>LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of <sup>177</sup>Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00033	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	87.50%	%	.	.	.	9 patients with paraganglioma.	.	.	.	.	2-9 cycles	.	.	"Recently, a study in 9 patients of metastatic paragangliomas (7 patients received prior <sup>177</sup>Lu-DOTATATE and 3 out of 7 patients failed prior <sup>177</sup>Lu-DOTATATE) treated with 225Ac-DOTATATE ( particle based radiotherapy targeting SSTRs) and concomitant capecitabine showed a high partial response of 50% (compared to < 25% with particle targeted radiotherapies) and stable disease in 37.5% with a disease control rate of 87.5%, without any grade 3/4 hematotoxicity, nephrotoxicity, or hepatotoxicity."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	89.60%	%	.	.	.	179 patients with paraganglioma.	.	.	.	.	1-11 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	84%	%	.	.	.	201 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	90%	%	.	.	.	330 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	76%	%	.	.	.	64 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	17-39 months	months	.	.	.	179 patients with paraganglioma.	.	.	.	.	1-11 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	10-91 months	months	.	.	.	4 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	37.1 months	months	.	.	.	2 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	31.8 months	months	.	.	.	330 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	19.1 months	months	.	.	.	36 patients with paraganglioma.	.	.	.	.	4 cycles	.	.	"The efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating <sup>177</sup>Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after <sup>177</sup>LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of <sup>177</sup>Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	22.7 months	months	.	.	.	18 patients with paraganglioma.	.	.	.	.	4 cycles	.	.	"The efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating <sup>177</sup>Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after <sup>177</sup>LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of <sup>177</sup>Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	15.4 months	months	.	.	.	18 patients with paraganglioma.	.	.	.	.	4 cycles	.	.	"The efficacy and safety data of the interim analysis of an open-label, single-arm phase 2 study evaluating <sup>177</sup>Lu-DOTATATE in paraganglioma patients conducted at the National Institutes of Health (NCT03206060) in 36 patients [(n=18, apparently sporadic cohort and n=18 in patients having germline variant in one of the genes encoding subunits of succinate dehydrogenase complex (SDHA=2, SDHB=15, SDHD=1)), SDHx cohort] after <sup>177</sup>LuDOTATATE therapy with 7.4 GBq every 8 weeks for 4 cycles. The progression-free survival at 6 months since initiation of <sup>177</sup>Lu-DOTATATE was 19.1 months (22.7 months in apparently sporadic cohort and 15.4 months in SDHx cohort) and overall survival was not reached in both cohorts (80). Per RECIST 1.1, overall, 86.1% patients showed partial response (13.9%) or stable disease (72.2%). In sporadic cohort; partial response was observed in 11.1% and stable disease in 88.9% patients whereas those in SDHx cohort were, 16.7% and 55.5%, respectively at the end of 6 months."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	17-39 months	months	.	.	.	179 patients with paraganglioma.	.	.	.	.	1-11 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	10-91 months	months	.	.	.	4 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	37.1 months	months	.	.	.	2 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Progression-free survival (PFS)	31.8 months	months	.	.	.	330 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	49.6-68.0 months	months	.	.	.	179 patients with paraganglioma.	.	.	.	.	1-11 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	54.5 months	months	.	.	.	201 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00027	Pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	74.3 months	months	.	.	.	330 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	49.6-68.0 months	months	.	.	.	179 patients with paraganglioma.	.	.	.	.	1-11 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	54.5 months	months	.	.	.	201 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00313	PDC_00045	Well-differentiated pancreatic neuroendocrine tumor	.	Identified from the Human Clinical Data	High Expreesion	Overall survival (OS)	74.3 months	months	.	.	.	330 patients with paraganglioma.	.	.	.	.	1-10 cycles	.	.	"The use of PRRT for patients with PPGLs who had high tumor SSTR expression has mainly been reported in retrospective small case series and the protocols varied in all these studies. So far, four meta-analyses (Taieb et al. and Satapathy et al. in 2019 as well as Su et al. and Marretta et al. in 2023) based on PRRT (<sup>177</sup>Lu/90Y-DOTAT-TATE/TOC) therapy have been reported. The reported number of pooled patients ranged from 179-330 without any complete response. The reported partial response ranged from 20-25% and stable disease from 59-70% giving an objective response rate range of 20-25% and disease control rate range of 8190%. The survival rates were reported by only 3 meta-analyses. The reported progression-free survival were 17-39 months in seven studies by Taieb et al., 10-91 months in 4 studies and a mean of 37.1 months in 2 studies by Satapathy et al., and a median of 31.8 months in 13 studies by Su et al. whereas overall survival were 49.6-68.0 months in 3 studies by Taieb et al., a mean of 54.5 months in 4 studies by Satapathy et al. and a median of 74.3 months in 11 studies by Su et al. Su et al. reports a pooled adverse events data in 274/330 patients which mentions a grade 3/4 hematotoxicity in 4.3% (grade 1-4, 22.3%) and grade 3/4 nephrotoxicity in 1.9% (grade 1-4, 1.9%), and myelodysplastic syndrome in 1 patient. Treatment discontinuation occurred in 4 patients due to thrombocytopenia (n=3) or nephrotoxicity (n=1)."	"Paragangliomas can metastasize, posing potential challenges in both symptomatic management and disease control. Systemic targeted radiotherapies using 131I-MIBG and <sup>177</sup>Lu-DOTATATE are a mainstay in the treatment of metastatic paragangliomas. This clinical scenario and discussion aim to enhance physicians' knowledge of the stepwise approach to treat these patients with paraganglioma targeted radiotherapies. It comprehensively discusses current approaches to selecting paraganglioma patients for targeted radiotherapies and how to choose between the two radiotherapies based on specific patient and tumor characteristics, when either therapy is feasible, or one is superior to another one. The safety, efficacy, toxicity profiles, and optimization of these radiotherapies are also discussed, along with other therapeutic options including radiotherapies, available for patients besides these two therapies. As conclusion, perspectives in radiotherapies of paraganglioma patients are outlined since they hold near future promising approaches that can improve patient outcomes."
REF00312	PDC_00285	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.96 &plusmn; 0.98 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00289	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.37 &plusmn; 0.32 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00290	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.47 &plusmn; 0.67 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00291	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.37 &plusmn; 0.42 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00292	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.44 &plusmn; 0.63 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00293	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11.02 &plusmn; 1.78 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00294	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.96 &plusmn; 2.41 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00295	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.04 &plusmn; 0.24 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00296	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11.63 &plusmn; 2.35 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00286	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.53 &plusmn; 0.53 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00287	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.41 &plusmn; 0.13 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00288	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.76 &plusmn; 0.33 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00285	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	17.94 &plusmn; 2.78 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00289	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.25 &plusmn; 1.75 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00290	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.51 &plusmn; 1.74 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00291	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.45 &plusmn; 1.09 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00292	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.83 &plusmn; 1.77 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00293	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00294	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.23 &plusmn; 1.65 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00295	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.91 &plusmn; 0.71 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00296	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00286	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	22.44 &plusmn; 2.21 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00287	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.93 &plusmn; 1.41 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00288	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.12 &plusmn; 0.45 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00285	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	38.72 &plusmn; 4.62 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00289	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	19.10 &plusmn; 2.94 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00290	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	32.44 &plusmn; 5.49 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00291	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	13.91 &plusmn; 2.61 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00292	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	17.84 &plusmn; 3.14 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00293	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00294	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.44 &plusmn; 2.41 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00295	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	13.49 &plusmn; 3.59 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00296	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00286	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	25.12 &plusmn; 2.04 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00287	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.25 &plusmn; 1.34 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00288	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	13.21 &plusmn; 1.15 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00285	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	27.24 &plusmn; 1.73 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00289	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	24.45 &plusmn; 2.04 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00290	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	30.12 &plusmn; 1.38 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00291	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	28.25 &plusmn; 3.12 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00292	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	20.36 &plusmn; 1.82 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00293	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00294	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	33.12 &plusmn; 3.84 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00295	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	26.34 &plusmn; 1.08 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00296	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00286	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	17.25 &plusmn; 2.31 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00287	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	12.93 &plusmn; 1.15 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00288	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.25 &plusmn; 2.08 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"To evaluated the in vitro anti-tumor activity of the conjugates, HER2-positive SK-BR-3, NCI-N87, HER2-negative MDA-MB-231 and normal MCF-10A cells were selected. As shown in Table 2, nearly all conjugates exhibited obvious anti-proliferation activity against SK-BR-3 cells, while most of the conjugates, except for Z6 and Z9, demonstrated different degrees of inhibitory activity on NCI-N87 cells. Taken together, Z8 and Z11 exhibited superior anti-tumor activity. The antiproliferative activity of Z8 against NCI-N87 cells (IC50 = 1.91 &plusmn; 0.71 uM) was comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 uM), while the antiproliferative activity of Z11 against SK-BR-3 cells (IC50 = 0.41 &plusmn; 0.13 uM) was comparable to that of CPT (IC50 = 0.26 &plusmn; 0.06 uM). Additionally, the IC50 values of these two conjugates against MDA-MB-231 and MCF-10A cells were significantly increased, showing their ability to selectively inhibit tumor cells. Based on the above results, Z8 and Z11, which exhibited better activity and apparent selectivity, were selected for subsequent studies."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00295	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Apoptosis rate	27.10%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	24 h	1 &micro;M	Flow cytometry assay	"The proapoptotic activity of Z8 was studied by flow cytometry combined with Annexin V-FITC/PI double staining. As shown in Fig. 4, after treatment with 1 uM Z8, the apoptosis rate of SK-BR-3 cells was approximately 27.1 % which increased to 41.1 % following treatment with 2 uM Z8 (4.4 % in the blank control group and 55.8 % in CPT group. These findings suggest that Z8 can significantly induce apoptosis in a dose-dependent manner."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00295	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Apoptosis rate	41.10%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	24 h	2 &micro;M	Flow cytometry assay	"The proapoptotic activity of Z8 was studied by flow cytometry combined with Annexin V-FITC/PI double staining. As shown in Fig. 4, after treatment with 1 uM Z8, the apoptosis rate of SK-BR-3 cells was approximately 27.1 % which increased to 41.1 % following treatment with 2 uM Z8 (4.4 % in the blank control group and 55.8 % in CPT group. These findings suggest that Z8 can significantly induce apoptosis in a dose-dependent manner."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00312	PDC_00295	Breast cancer	SK-BR-3 tumor-bearing nude mice xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	60% (Day 14)	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	Injected via tail vein every t hree days	8 &micro;mol/kg	.	"To study the in vivo anti-tumor activity of Z8, SK-BR-3 tumor bearing nude mice were administered once every three days. As shown in Fig. 11A-11D, CPT and Z8 demonstrated significant inhibitory effects on SK-BR-3 tumor growth, with the Z8 group exhibiting more pronounced inhibition compared to CPT. Notably, the average tumor volume and weight in the Z8 group were the smallest among all groups, including the control and CPT groups. Moreover, to further study the toxicity of CPT and Z8, serums of mice were collected for blood biochemical analysis. As shown in Fig. 11E-H, treatment with both CPT and Z8 resulted in increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), but the effect of Z8 group was relatively low, indicating that Z8 was safer than CPT in vivo. Furthermore, in CPT group, urea nitrogen levels increased significantly, whereas no significant change was observed in the Z8 group, indicating potential renal function impairment following CPT treatment, whereas Z8 showed better safety in this regard. Additionally, the levels of alkaline phosphatase (ALP), total protein (TP), albumin (ALB), globulin (GLOB) and creatinine (CREA) did not significantly differ between the control group and the treatment groups. Finally, compared to the control group, histological examination using H&E staining (Hematoxylin and Eosin staining) of the major organs in the treatment group did not reveal obvious cell necrosis and inflammatory cell infiltration, indicating that Z8 would not bring additional toxicity."	"In the previous study, we focused on the discovery of novel cell targeting peptides, leading to the identification of the preferred HER2-targeting peptide P1 (NPNWGRSWYNQRFK) derived from pertuzumab, with the Kd of 5.70 10-6 M. Here, we designed and synthesized a series of PDCs choosing Camptothecin (CPT) as the payload and P1 as the peptide carrier. We aimed to discover novel PDC molecules with potent inhibitory activity and selectivity targeting HER2 for effective cancer treatment. Conjugate Z8, which balanced the activity and the biosafety, showed good antiproliferative activity (IC50 = 1.91 &plusmn; 0.71 M), comparable to that of CPT (IC50 = 2.10 &plusmn; 1.34 M), against NCI-N87 cells. Moreover, subsequent verification tests indicated that Z8 operated through a mechanism similar to CPT, but the results from in vivo anti-tumor activity assay suggested that Z8 exhibited greater safety compared to CPT to some extent. These findings highlight Z8 as a promising candidate for further investigation in the treatment of HER2-positive tumors."
REF00310	PDC_00124	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	4 nM	nM	.	.	.	.	Ovarian serous adenocarcinoma	OVCAR-3 cell	.	.	3 days	.	.	"GI50s are summarised in Table 1. Our cell panel consisted of LHRH receptor-positive (OVCAR-3) and receptor-negative (SK-OV-3) ovarian cancer cell lines used in Zoptarelin doxorubicin's preclinical development studies. Non-cancerous human ovarian (H-6036) and lung fibroblast (MRC-5) cell lines were also included for selectivity comparison. Paclitaxel, a first-line chemotherapeutic drug used for ovarian cancer, was observed to be highly cytotoxic against all cell lines, including non-cancerous ovarian and human fibroblasts (GI50s 1-5 nM). Unsurprisingly, common and serious side-effects experienced by more than 50% patients dosed with this drug included anaemia, neutropenia, peripheral neuropathy, nausea, vomiting, myalgia, arthralgia and alopecia. Similarly, doxorubicin was also shown to be non-specific towards all the cell lines (GI50s 60-311 nM), below the reported average 631 nM GI50 in a study involving 39 cancer cell lines. It is noteworthy that doxorubicin exhibited moderate GI50s of 311 and 218 nM against OVCAR-3 and SK-OV-3, respectively, supporting earlier in vitro data. Tubulin binder MMAE was found to be ultra-toxic against all cell lines (GI50s 0.5-1.1 nM), supporting the findings from an earlier report. It is therefore unsurprising that MMAE has never been approved as a drug on its own. The LHRH analog and carrier peptide, D-Cys6-LHRH, was inactive against all cell lines (GI50s >50,000 nM)."	"Ovarian cancer is the most deadly female gynaecological malignancy in developed countries and new treatments are urgently needed. The luteinising hormone releasing hormone (LHRH) peptide drug conjugate Zoptarelin doxorubicin is one such potential new drug modality that entered clinical trials for treating LHRH receptor-positive gynaecological cancers. However, development stopped after disappointing Phase 3 results in 2017. We believe the lack of efficacy was due to linker instability and payload potency. In this work, we replaced its linker-toxin with vedotin (MC-VC-PABC-MMAE), yielding the novel peptide drug conjugate D-Cys6-LHRH vedotin. A GI50 and cell specificity comparison against cancerous and non-cancerous ovarian cell lines showed significantly superior bioactivity and selectivity over Zoptarelin doxorubicin (GI50 4 vs. 453 nM) and other chemotherapeutic drugs used for treating ovarian cancers. Our results suggest D-Cys6-LHRH vedotin can potentially be used as a treatment for ovarian cancer."
REF00310	PDC_00124	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	49 nM	nM	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	3 days	.	.	"GI50s are summarised in Table 1. Our cell panel consisted of LHRH receptor-positive (OVCAR-3) and receptor-negative (SK-OV-3) ovarian cancer cell lines used in Zoptarelin doxorubicin's preclinical development studies. Non-cancerous human ovarian (H-6036) and lung fibroblast (MRC-5) cell lines were also included for selectivity comparison. Paclitaxel, a first-line chemotherapeutic drug used for ovarian cancer, was observed to be highly cytotoxic against all cell lines, including non-cancerous ovarian and human fibroblasts (GI50s 1-5 nM). Unsurprisingly, common and serious side-effects experienced by more than 50% patients dosed with this drug included anaemia, neutropenia, peripheral neuropathy, nausea, vomiting, myalgia, arthralgia and alopecia. Similarly, doxorubicin was also shown to be non-specific towards all the cell lines (GI50s 60-311 nM), below the reported average 631 nM GI50 in a study involving 39 cancer cell lines. It is noteworthy that doxorubicin exhibited moderate GI50s of 311 and 218 nM against OVCAR-3 and SK-OV-3, respectively, supporting earlier in vitro data. Tubulin binder MMAE was found to be ultra-toxic against all cell lines (GI50s 0.5-1.1 nM), supporting the findings from an earlier report. It is therefore unsurprising that MMAE has never been approved as a drug on its own. The LHRH analog and carrier peptide, D-Cys6-LHRH, was inactive against all cell lines (GI50s >50,000 nM)."	"Ovarian cancer is the most deadly female gynaecological malignancy in developed countries and new treatments are urgently needed. The luteinising hormone releasing hormone (LHRH) peptide drug conjugate Zoptarelin doxorubicin is one such potential new drug modality that entered clinical trials for treating LHRH receptor-positive gynaecological cancers. However, development stopped after disappointing Phase 3 results in 2017. We believe the lack of efficacy was due to linker instability and payload potency. In this work, we replaced its linker-toxin with vedotin (MC-VC-PABC-MMAE), yielding the novel peptide drug conjugate D-Cys6-LHRH vedotin. A GI50 and cell specificity comparison against cancerous and non-cancerous ovarian cell lines showed significantly superior bioactivity and selectivity over Zoptarelin doxorubicin (GI50 4 vs. 453 nM) and other chemotherapeutic drugs used for treating ovarian cancers. Our results suggest D-Cys6-LHRH vedotin can potentially be used as a treatment for ovarian cancer."
REF00310	PDC_00124	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	52 nM	nM	.	.	.	.	Normal	H-6036 cell	.	.	3 days	.	.	"GI50s are summarised in Table 1. Our cell panel consisted of LHRH receptor-positive (OVCAR-3) and receptor-negative (SK-OV-3) ovarian cancer cell lines used in Zoptarelin doxorubicin's preclinical development studies. Non-cancerous human ovarian (H-6036) and lung fibroblast (MRC-5) cell lines were also included for selectivity comparison. Paclitaxel, a first-line chemotherapeutic drug used for ovarian cancer, was observed to be highly cytotoxic against all cell lines, including non-cancerous ovarian and human fibroblasts (GI50s 1-5 nM). Unsurprisingly, common and serious side-effects experienced by more than 50% patients dosed with this drug included anaemia, neutropenia, peripheral neuropathy, nausea, vomiting, myalgia, arthralgia and alopecia. Similarly, doxorubicin was also shown to be non-specific towards all the cell lines (GI50s 60-311 nM), below the reported average 631 nM GI50 in a study involving 39 cancer cell lines. It is noteworthy that doxorubicin exhibited moderate GI50s of 311 and 218 nM against OVCAR-3 and SK-OV-3, respectively, supporting earlier in vitro data. Tubulin binder MMAE was found to be ultra-toxic against all cell lines (GI50s 0.5-1.1 nM), supporting the findings from an earlier report. It is therefore unsurprising that MMAE has never been approved as a drug on its own. The LHRH analog and carrier peptide, D-Cys6-LHRH, was inactive against all cell lines (GI50s >50,000 nM)."	"Ovarian cancer is the most deadly female gynaecological malignancy in developed countries and new treatments are urgently needed. The luteinising hormone releasing hormone (LHRH) peptide drug conjugate Zoptarelin doxorubicin is one such potential new drug modality that entered clinical trials for treating LHRH receptor-positive gynaecological cancers. However, development stopped after disappointing Phase 3 results in 2017. We believe the lack of efficacy was due to linker instability and payload potency. In this work, we replaced its linker-toxin with vedotin (MC-VC-PABC-MMAE), yielding the novel peptide drug conjugate D-Cys6-LHRH vedotin. A GI50 and cell specificity comparison against cancerous and non-cancerous ovarian cell lines showed significantly superior bioactivity and selectivity over Zoptarelin doxorubicin (GI50 4 vs. 453 nM) and other chemotherapeutic drugs used for treating ovarian cancers. Our results suggest D-Cys6-LHRH vedotin can potentially be used as a treatment for ovarian cancer."
REF00310	PDC_00124	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	191 nM	nM	.	.	.	.	Normal	MRC-5 cell	.	.	3 days	.	.	"GI50s are summarised in Table 1. Our cell panel consisted of LHRH receptor-positive (OVCAR-3) and receptor-negative (SK-OV-3) ovarian cancer cell lines used in Zoptarelin doxorubicin's preclinical development studies. Non-cancerous human ovarian (H-6036) and lung fibroblast (MRC-5) cell lines were also included for selectivity comparison. Paclitaxel, a first-line chemotherapeutic drug used for ovarian cancer, was observed to be highly cytotoxic against all cell lines, including non-cancerous ovarian and human fibroblasts (GI50s 1-5 nM). Unsurprisingly, common and serious side-effects experienced by more than 50% patients dosed with this drug included anaemia, neutropenia, peripheral neuropathy, nausea, vomiting, myalgia, arthralgia and alopecia. Similarly, doxorubicin was also shown to be non-specific towards all the cell lines (GI50s 60-311 nM), below the reported average 631 nM GI50 in a study involving 39 cancer cell lines. It is noteworthy that doxorubicin exhibited moderate GI50s of 311 and 218 nM against OVCAR-3 and SK-OV-3, respectively, supporting earlier in vitro data. Tubulin binder MMAE was found to be ultra-toxic against all cell lines (GI50s 0.5-1.1 nM), supporting the findings from an earlier report. It is therefore unsurprising that MMAE has never been approved as a drug on its own. The LHRH analog and carrier peptide, D-Cys6-LHRH, was inactive against all cell lines (GI50s >50,000 nM)."	"Ovarian cancer is the most deadly female gynaecological malignancy in developed countries and new treatments are urgently needed. The luteinising hormone releasing hormone (LHRH) peptide drug conjugate Zoptarelin doxorubicin is one such potential new drug modality that entered clinical trials for treating LHRH receptor-positive gynaecological cancers. However, development stopped after disappointing Phase 3 results in 2017. We believe the lack of efficacy was due to linker instability and payload potency. In this work, we replaced its linker-toxin with vedotin (MC-VC-PABC-MMAE), yielding the novel peptide drug conjugate D-Cys6-LHRH vedotin. A GI50 and cell specificity comparison against cancerous and non-cancerous ovarian cell lines showed significantly superior bioactivity and selectivity over Zoptarelin doxorubicin (GI50 4 vs. 453 nM) and other chemotherapeutic drugs used for treating ovarian cancers. Our results suggest D-Cys6-LHRH vedotin can potentially be used as a treatment for ovarian cancer."
REF00309	PDC_00323	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	95%	%	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	0.47 &micro;M	Flow cytometry assay	"Analysis of dot-plots suggests that the rL-A9 peptide alone does not exert any significant cytotoxic effects on either HER2-positive, SKOV3 cells or HER2-negative, MDA-MB-231 cells at any of the investigated concentrations. In contrast, incubation of drug DOX with either of the cells resulted in enhanced cell death with a negligible viable population even at lower concentrations. However, it was observed that the peptide-drug conjugate, rL-A9-DOX had a concentration-dependent impact on cell death (SKOV3 cells). Notably, nearly half of the cell population died at 3.75 uM. At a concentration of 15 uM, there were only 5% viable SKOV3 cells. The higher percent of the viable cell population was observed at corresponding concentrations in the case of incubation of rL-A9-DOX with HER2-negative, MDA-MB-231 cells. Comparative data of viability in two different cell lines is presented in Figure 6 for the peptide-drug conjugate, rL-A9-DOX."	"The peptide A9 has been reported in the literature to exhibit high affinity and specificity towards the HER2 receptor. In our previous report, we observed the retro variant of A9 peptide, rL-A9, to be a promising molecule for targeting HER2-expressing breast cancer cells. The present study, thus aimed at designing and synthesis of a peptide-drug conjugate by linking the rL-A9 peptide with DOX. A linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) was utilized for conjugation of DOX at one end and the peptide at the other end. The N-hydroxysuccinimidyl ester group of SMCC was conjugated with the amine (-NH2) group of DOX resulting in the formation of amide bond. The thiol (-SH) functionality was introduced by coupling cysteine amino acid at the N-terminus of the rL-A9 peptide for covalent linkage with the maleimide group of SMCC. Successful synthesis of the conjugate was confirmed by MALDI-TOF mass spectrometry. Cytotoxicity, cellular uptake and internalization of the peptide, drug and peptide-drug conjugate were assessed in SKOV3 cells using flow cytometry and confocal fluorescence microscopy."
REF00309	PDC_00323	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	91%	%	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	0.94 &micro;M	Flow cytometry assay	"Analysis of dot-plots suggests that the rL-A9 peptide alone does not exert any significant cytotoxic effects on either HER2-positive, SKOV3 cells or HER2-negative, MDA-MB-231 cells at any of the investigated concentrations. In contrast, incubation of drug DOX with either of the cells resulted in enhanced cell death with a negligible viable population even at lower concentrations. However, it was observed that the peptide-drug conjugate, rL-A9-DOX had a concentration-dependent impact on cell death (SKOV3 cells). Notably, nearly half of the cell population died at 3.75 uM. At a concentration of 15 uM, there were only 5% viable SKOV3 cells. The higher percent of the viable cell population was observed at corresponding concentrations in the case of incubation of rL-A9-DOX with HER2-negative, MDA-MB-231 cells. Comparative data of viability in two different cell lines is presented in Figure 6 for the peptide-drug conjugate, rL-A9-DOX."	"The peptide A9 has been reported in the literature to exhibit high affinity and specificity towards the HER2 receptor. In our previous report, we observed the retro variant of A9 peptide, rL-A9, to be a promising molecule for targeting HER2-expressing breast cancer cells. The present study, thus aimed at designing and synthesis of a peptide-drug conjugate by linking the rL-A9 peptide with DOX. A linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) was utilized for conjugation of DOX at one end and the peptide at the other end. The N-hydroxysuccinimidyl ester group of SMCC was conjugated with the amine (-NH2) group of DOX resulting in the formation of amide bond. The thiol (-SH) functionality was introduced by coupling cysteine amino acid at the N-terminus of the rL-A9 peptide for covalent linkage with the maleimide group of SMCC. Successful synthesis of the conjugate was confirmed by MALDI-TOF mass spectrometry. Cytotoxicity, cellular uptake and internalization of the peptide, drug and peptide-drug conjugate were assessed in SKOV3 cells using flow cytometry and confocal fluorescence microscopy."
REF00309	PDC_00323	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	67%	%	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	1.87 &micro;M	Flow cytometry assay	"Analysis of dot-plots suggests that the rL-A9 peptide alone does not exert any significant cytotoxic effects on either HER2-positive, SKOV3 cells or HER2-negative, MDA-MB-231 cells at any of the investigated concentrations. In contrast, incubation of drug DOX with either of the cells resulted in enhanced cell death with a negligible viable population even at lower concentrations. However, it was observed that the peptide-drug conjugate, rL-A9-DOX had a concentration-dependent impact on cell death (SKOV3 cells). Notably, nearly half of the cell population died at 3.75 uM. At a concentration of 15 uM, there were only 5% viable SKOV3 cells. The higher percent of the viable cell population was observed at corresponding concentrations in the case of incubation of rL-A9-DOX with HER2-negative, MDA-MB-231 cells. Comparative data of viability in two different cell lines is presented in Figure 6 for the peptide-drug conjugate, rL-A9-DOX."	"The peptide A9 has been reported in the literature to exhibit high affinity and specificity towards the HER2 receptor. In our previous report, we observed the retro variant of A9 peptide, rL-A9, to be a promising molecule for targeting HER2-expressing breast cancer cells. The present study, thus aimed at designing and synthesis of a peptide-drug conjugate by linking the rL-A9 peptide with DOX. A linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) was utilized for conjugation of DOX at one end and the peptide at the other end. The N-hydroxysuccinimidyl ester group of SMCC was conjugated with the amine (-NH2) group of DOX resulting in the formation of amide bond. The thiol (-SH) functionality was introduced by coupling cysteine amino acid at the N-terminus of the rL-A9 peptide for covalent linkage with the maleimide group of SMCC. Successful synthesis of the conjugate was confirmed by MALDI-TOF mass spectrometry. Cytotoxicity, cellular uptake and internalization of the peptide, drug and peptide-drug conjugate were assessed in SKOV3 cells using flow cytometry and confocal fluorescence microscopy."
REF00309	PDC_00323	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	49%	%	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	3.75 &micro;M	Flow cytometry assay	"Analysis of dot-plots suggests that the rL-A9 peptide alone does not exert any significant cytotoxic effects on either HER2-positive, SKOV3 cells or HER2-negative, MDA-MB-231 cells at any of the investigated concentrations. In contrast, incubation of drug DOX with either of the cells resulted in enhanced cell death with a negligible viable population even at lower concentrations. However, it was observed that the peptide-drug conjugate, rL-A9-DOX had a concentration-dependent impact on cell death (SKOV3 cells). Notably, nearly half of the cell population died at 3.75 uM. At a concentration of 15 uM, there were only 5% viable SKOV3 cells. The higher percent of the viable cell population was observed at corresponding concentrations in the case of incubation of rL-A9-DOX with HER2-negative, MDA-MB-231 cells. Comparative data of viability in two different cell lines is presented in Figure 6 for the peptide-drug conjugate, rL-A9-DOX."	"The peptide A9 has been reported in the literature to exhibit high affinity and specificity towards the HER2 receptor. In our previous report, we observed the retro variant of A9 peptide, rL-A9, to be a promising molecule for targeting HER2-expressing breast cancer cells. The present study, thus aimed at designing and synthesis of a peptide-drug conjugate by linking the rL-A9 peptide with DOX. A linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) was utilized for conjugation of DOX at one end and the peptide at the other end. The N-hydroxysuccinimidyl ester group of SMCC was conjugated with the amine (-NH2) group of DOX resulting in the formation of amide bond. The thiol (-SH) functionality was introduced by coupling cysteine amino acid at the N-terminus of the rL-A9 peptide for covalent linkage with the maleimide group of SMCC. Successful synthesis of the conjugate was confirmed by MALDI-TOF mass spectrometry. Cytotoxicity, cellular uptake and internalization of the peptide, drug and peptide-drug conjugate were assessed in SKOV3 cells using flow cytometry and confocal fluorescence microscopy."
REF00309	PDC_00323	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	26%	%	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	7.5 &micro;M	Flow cytometry assay	"Analysis of dot-plots suggests that the rL-A9 peptide alone does not exert any significant cytotoxic effects on either HER2-positive, SKOV3 cells or HER2-negative, MDA-MB-231 cells at any of the investigated concentrations. In contrast, incubation of drug DOX with either of the cells resulted in enhanced cell death with a negligible viable population even at lower concentrations. However, it was observed that the peptide-drug conjugate, rL-A9-DOX had a concentration-dependent impact on cell death (SKOV3 cells). Notably, nearly half of the cell population died at 3.75 uM. At a concentration of 15 uM, there were only 5% viable SKOV3 cells. The higher percent of the viable cell population was observed at corresponding concentrations in the case of incubation of rL-A9-DOX with HER2-negative, MDA-MB-231 cells. Comparative data of viability in two different cell lines is presented in Figure 6 for the peptide-drug conjugate, rL-A9-DOX."	"The peptide A9 has been reported in the literature to exhibit high affinity and specificity towards the HER2 receptor. In our previous report, we observed the retro variant of A9 peptide, rL-A9, to be a promising molecule for targeting HER2-expressing breast cancer cells. The present study, thus aimed at designing and synthesis of a peptide-drug conjugate by linking the rL-A9 peptide with DOX. A linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) was utilized for conjugation of DOX at one end and the peptide at the other end. The N-hydroxysuccinimidyl ester group of SMCC was conjugated with the amine (-NH2) group of DOX resulting in the formation of amide bond. The thiol (-SH) functionality was introduced by coupling cysteine amino acid at the N-terminus of the rL-A9 peptide for covalent linkage with the maleimide group of SMCC. Successful synthesis of the conjugate was confirmed by MALDI-TOF mass spectrometry. Cytotoxicity, cellular uptake and internalization of the peptide, drug and peptide-drug conjugate were assessed in SKOV3 cells using flow cytometry and confocal fluorescence microscopy."
REF00309	PDC_00323	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	7%	%	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	15 &micro;M	Flow cytometry assay	"Analysis of dot-plots suggests that the rL-A9 peptide alone does not exert any significant cytotoxic effects on either HER2-positive, SKOV3 cells or HER2-negative, MDA-MB-231 cells at any of the investigated concentrations. In contrast, incubation of drug DOX with either of the cells resulted in enhanced cell death with a negligible viable population even at lower concentrations. However, it was observed that the peptide-drug conjugate, rL-A9-DOX had a concentration-dependent impact on cell death (SKOV3 cells). Notably, nearly half of the cell population died at 3.75 uM. At a concentration of 15 uM, there were only 5% viable SKOV3 cells. The higher percent of the viable cell population was observed at corresponding concentrations in the case of incubation of rL-A9-DOX with HER2-negative, MDA-MB-231 cells. Comparative data of viability in two different cell lines is presented in Figure 6 for the peptide-drug conjugate, rL-A9-DOX."	"The peptide A9 has been reported in the literature to exhibit high affinity and specificity towards the HER2 receptor. In our previous report, we observed the retro variant of A9 peptide, rL-A9, to be a promising molecule for targeting HER2-expressing breast cancer cells. The present study, thus aimed at designing and synthesis of a peptide-drug conjugate by linking the rL-A9 peptide with DOX. A linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) was utilized for conjugation of DOX at one end and the peptide at the other end. The N-hydroxysuccinimidyl ester group of SMCC was conjugated with the amine (-NH2) group of DOX resulting in the formation of amide bond. The thiol (-SH) functionality was introduced by coupling cysteine amino acid at the N-terminus of the rL-A9 peptide for covalent linkage with the maleimide group of SMCC. Successful synthesis of the conjugate was confirmed by MALDI-TOF mass spectrometry. Cytotoxicity, cellular uptake and internalization of the peptide, drug and peptide-drug conjugate were assessed in SKOV3 cells using flow cytometry and confocal fluorescence microscopy."
REF00309	PDC_00323	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	97%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	0.47 &micro;M	Flow cytometry assay	"Analysis of dot-plots suggests that the rL-A9 peptide alone does not exert any significant cytotoxic effects on either HER2-positive, SKOV3 cells or HER2-negative, MDA-MB-231 cells at any of the investigated concentrations. In contrast, incubation of drug DOX with either of the cells resulted in enhanced cell death with a negligible viable population even at lower concentrations. However, it was observed that the peptide-drug conjugate, rL-A9-DOX had a concentration-dependent impact on cell death (SKOV3 cells). Notably, nearly half of the cell population died at 3.75 uM. At a concentration of 15 uM, there were only 5% viable SKOV3 cells. The higher percent of the viable cell population was observed at corresponding concentrations in the case of incubation of rL-A9-DOX with HER2-negative, MDA-MB-231 cells. Comparative data of viability in two different cell lines is presented in Figure 6 for the peptide-drug conjugate, rL-A9-DOX."	"The peptide A9 has been reported in the literature to exhibit high affinity and specificity towards the HER2 receptor. In our previous report, we observed the retro variant of A9 peptide, rL-A9, to be a promising molecule for targeting HER2-expressing breast cancer cells. The present study, thus aimed at designing and synthesis of a peptide-drug conjugate by linking the rL-A9 peptide with DOX. A linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) was utilized for conjugation of DOX at one end and the peptide at the other end. The N-hydroxysuccinimidyl ester group of SMCC was conjugated with the amine (-NH2) group of DOX resulting in the formation of amide bond. The thiol (-SH) functionality was introduced by coupling cysteine amino acid at the N-terminus of the rL-A9 peptide for covalent linkage with the maleimide group of SMCC. Successful synthesis of the conjugate was confirmed by MALDI-TOF mass spectrometry. Cytotoxicity, cellular uptake and internalization of the peptide, drug and peptide-drug conjugate were assessed in SKOV3 cells using flow cytometry and confocal fluorescence microscopy."
REF00309	PDC_00323	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	96%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	0.94 &micro;M	Flow cytometry assay	"Analysis of dot-plots suggests that the rL-A9 peptide alone does not exert any significant cytotoxic effects on either HER2-positive, SKOV3 cells or HER2-negative, MDA-MB-231 cells at any of the investigated concentrations. In contrast, incubation of drug DOX with either of the cells resulted in enhanced cell death with a negligible viable population even at lower concentrations. However, it was observed that the peptide-drug conjugate, rL-A9-DOX had a concentration-dependent impact on cell death (SKOV3 cells). Notably, nearly half of the cell population died at 3.75 uM. At a concentration of 15 uM, there were only 5% viable SKOV3 cells. The higher percent of the viable cell population was observed at corresponding concentrations in the case of incubation of rL-A9-DOX with HER2-negative, MDA-MB-231 cells. Comparative data of viability in two different cell lines is presented in Figure 6 for the peptide-drug conjugate, rL-A9-DOX."	"The peptide A9 has been reported in the literature to exhibit high affinity and specificity towards the HER2 receptor. In our previous report, we observed the retro variant of A9 peptide, rL-A9, to be a promising molecule for targeting HER2-expressing breast cancer cells. The present study, thus aimed at designing and synthesis of a peptide-drug conjugate by linking the rL-A9 peptide with DOX. A linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) was utilized for conjugation of DOX at one end and the peptide at the other end. The N-hydroxysuccinimidyl ester group of SMCC was conjugated with the amine (-NH2) group of DOX resulting in the formation of amide bond. The thiol (-SH) functionality was introduced by coupling cysteine amino acid at the N-terminus of the rL-A9 peptide for covalent linkage with the maleimide group of SMCC. Successful synthesis of the conjugate was confirmed by MALDI-TOF mass spectrometry. Cytotoxicity, cellular uptake and internalization of the peptide, drug and peptide-drug conjugate were assessed in SKOV3 cells using flow cytometry and confocal fluorescence microscopy."
REF00309	PDC_00323	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	94%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	1.87 &micro;M	Flow cytometry assay	"Analysis of dot-plots suggests that the rL-A9 peptide alone does not exert any significant cytotoxic effects on either HER2-positive, SKOV3 cells or HER2-negative, MDA-MB-231 cells at any of the investigated concentrations. In contrast, incubation of drug DOX with either of the cells resulted in enhanced cell death with a negligible viable population even at lower concentrations. However, it was observed that the peptide-drug conjugate, rL-A9-DOX had a concentration-dependent impact on cell death (SKOV3 cells). Notably, nearly half of the cell population died at 3.75 uM. At a concentration of 15 uM, there were only 5% viable SKOV3 cells. The higher percent of the viable cell population was observed at corresponding concentrations in the case of incubation of rL-A9-DOX with HER2-negative, MDA-MB-231 cells. Comparative data of viability in two different cell lines is presented in Figure 6 for the peptide-drug conjugate, rL-A9-DOX."	"The peptide A9 has been reported in the literature to exhibit high affinity and specificity towards the HER2 receptor. In our previous report, we observed the retro variant of A9 peptide, rL-A9, to be a promising molecule for targeting HER2-expressing breast cancer cells. The present study, thus aimed at designing and synthesis of a peptide-drug conjugate by linking the rL-A9 peptide with DOX. A linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) was utilized for conjugation of DOX at one end and the peptide at the other end. The N-hydroxysuccinimidyl ester group of SMCC was conjugated with the amine (-NH2) group of DOX resulting in the formation of amide bond. The thiol (-SH) functionality was introduced by coupling cysteine amino acid at the N-terminus of the rL-A9 peptide for covalent linkage with the maleimide group of SMCC. Successful synthesis of the conjugate was confirmed by MALDI-TOF mass spectrometry. Cytotoxicity, cellular uptake and internalization of the peptide, drug and peptide-drug conjugate were assessed in SKOV3 cells using flow cytometry and confocal fluorescence microscopy."
REF00309	PDC_00323	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	87%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	3.75 &micro;M	Flow cytometry assay	"Analysis of dot-plots suggests that the rL-A9 peptide alone does not exert any significant cytotoxic effects on either HER2-positive, SKOV3 cells or HER2-negative, MDA-MB-231 cells at any of the investigated concentrations. In contrast, incubation of drug DOX with either of the cells resulted in enhanced cell death with a negligible viable population even at lower concentrations. However, it was observed that the peptide-drug conjugate, rL-A9-DOX had a concentration-dependent impact on cell death (SKOV3 cells). Notably, nearly half of the cell population died at 3.75 uM. At a concentration of 15 uM, there were only 5% viable SKOV3 cells. The higher percent of the viable cell population was observed at corresponding concentrations in the case of incubation of rL-A9-DOX with HER2-negative, MDA-MB-231 cells. Comparative data of viability in two different cell lines is presented in Figure 6 for the peptide-drug conjugate, rL-A9-DOX."	"The peptide A9 has been reported in the literature to exhibit high affinity and specificity towards the HER2 receptor. In our previous report, we observed the retro variant of A9 peptide, rL-A9, to be a promising molecule for targeting HER2-expressing breast cancer cells. The present study, thus aimed at designing and synthesis of a peptide-drug conjugate by linking the rL-A9 peptide with DOX. A linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) was utilized for conjugation of DOX at one end and the peptide at the other end. The N-hydroxysuccinimidyl ester group of SMCC was conjugated with the amine (-NH2) group of DOX resulting in the formation of amide bond. The thiol (-SH) functionality was introduced by coupling cysteine amino acid at the N-terminus of the rL-A9 peptide for covalent linkage with the maleimide group of SMCC. Successful synthesis of the conjugate was confirmed by MALDI-TOF mass spectrometry. Cytotoxicity, cellular uptake and internalization of the peptide, drug and peptide-drug conjugate were assessed in SKOV3 cells using flow cytometry and confocal fluorescence microscopy."
REF00309	PDC_00323	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	33%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	7.5 &micro;M	Flow cytometry assay	"Analysis of dot-plots suggests that the rL-A9 peptide alone does not exert any significant cytotoxic effects on either HER2-positive, SKOV3 cells or HER2-negative, MDA-MB-231 cells at any of the investigated concentrations. In contrast, incubation of drug DOX with either of the cells resulted in enhanced cell death with a negligible viable population even at lower concentrations. However, it was observed that the peptide-drug conjugate, rL-A9-DOX had a concentration-dependent impact on cell death (SKOV3 cells). Notably, nearly half of the cell population died at 3.75 uM. At a concentration of 15 uM, there were only 5% viable SKOV3 cells. The higher percent of the viable cell population was observed at corresponding concentrations in the case of incubation of rL-A9-DOX with HER2-negative, MDA-MB-231 cells. Comparative data of viability in two different cell lines is presented in Figure 6 for the peptide-drug conjugate, rL-A9-DOX."	"The peptide A9 has been reported in the literature to exhibit high affinity and specificity towards the HER2 receptor. In our previous report, we observed the retro variant of A9 peptide, rL-A9, to be a promising molecule for targeting HER2-expressing breast cancer cells. The present study, thus aimed at designing and synthesis of a peptide-drug conjugate by linking the rL-A9 peptide with DOX. A linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) was utilized for conjugation of DOX at one end and the peptide at the other end. The N-hydroxysuccinimidyl ester group of SMCC was conjugated with the amine (-NH2) group of DOX resulting in the formation of amide bond. The thiol (-SH) functionality was introduced by coupling cysteine amino acid at the N-terminus of the rL-A9 peptide for covalent linkage with the maleimide group of SMCC. Successful synthesis of the conjugate was confirmed by MALDI-TOF mass spectrometry. Cytotoxicity, cellular uptake and internalization of the peptide, drug and peptide-drug conjugate were assessed in SKOV3 cells using flow cytometry and confocal fluorescence microscopy."
REF00309	PDC_00323	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	13%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	15 &micro;M	Flow cytometry assay	"Analysis of dot-plots suggests that the rL-A9 peptide alone does not exert any significant cytotoxic effects on either HER2-positive, SKOV3 cells or HER2-negative, MDA-MB-231 cells at any of the investigated concentrations. In contrast, incubation of drug DOX with either of the cells resulted in enhanced cell death with a negligible viable population even at lower concentrations. However, it was observed that the peptide-drug conjugate, rL-A9-DOX had a concentration-dependent impact on cell death (SKOV3 cells). Notably, nearly half of the cell population died at 3.75 uM. At a concentration of 15 uM, there were only 5% viable SKOV3 cells. The higher percent of the viable cell population was observed at corresponding concentrations in the case of incubation of rL-A9-DOX with HER2-negative, MDA-MB-231 cells. Comparative data of viability in two different cell lines is presented in Figure 6 for the peptide-drug conjugate, rL-A9-DOX."	"The peptide A9 has been reported in the literature to exhibit high affinity and specificity towards the HER2 receptor. In our previous report, we observed the retro variant of A9 peptide, rL-A9, to be a promising molecule for targeting HER2-expressing breast cancer cells. The present study, thus aimed at designing and synthesis of a peptide-drug conjugate by linking the rL-A9 peptide with DOX. A linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) was utilized for conjugation of DOX at one end and the peptide at the other end. The N-hydroxysuccinimidyl ester group of SMCC was conjugated with the amine (-NH2) group of DOX resulting in the formation of amide bond. The thiol (-SH) functionality was introduced by coupling cysteine amino acid at the N-terminus of the rL-A9 peptide for covalent linkage with the maleimide group of SMCC. Successful synthesis of the conjugate was confirmed by MALDI-TOF mass spectrometry. Cytotoxicity, cellular uptake and internalization of the peptide, drug and peptide-drug conjugate were assessed in SKOV3 cells using flow cytometry and confocal fluorescence microscopy."
REF00308	PDC_00308	Glioma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.26 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U87 cell	.	.	48 h	.	MTT assay	"The coupling of peptides with chemotherapeutic drugs often increased the solubility of the drugs, so the solubility of peptide-drug conjugates was determined, and the results were shown in Fig. S9. DOX free base exhibited poor solubility, with a solubility of approximately 0.22 &plusmn; 0.03 mg/mL in PBS. However, upon formation of a peptide-drug conjugate, the hydrophilicity of the peptide significantly enhanced the solubility of DOX. The solubility of pHA-AHX-VAP-DOX and pHA-AOHX-VAP-DOX drastically increased to 7.09 &plusmn; 0.15 mg/mL and 17.29 &plusmn; 0.43 mg/mL, which was 32-fold and 78-fold higher than that of the DOX free base, respectively. The improved solubility performance was consistent with their LogP values predicted by the ALOGPS 2.1 program."	"The existence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) greatly limits the application of chemotherapy in glioma. To address this challenge, an optimal drug delivery system must efficiently cross the BBB/BBTB and specifically deliver therapeutic drugs into glioma cells while minimizing systemic toxicity. Here we demonstrated that glucose-regulated protein 78 (GRP78) and dopamine receptor D2 were highly expressed in patient-derived glioma tissues, and dopamine receptors were highly expressed on the BBB. Subsequently, we synthesized a novel Y-shaped peptide and compared the effects of different linkers on the receptor affinity and targeting ability of the peptide. A peptide-drug conjugate (pHA-AOHX-VAP-doxorubicin conjugate, pHA-AOHX-VAP-DOX) with a better affinity for glioma cells and higher solubility was derived for glioma treatment. pHA-AOHX-VAP-DOX could cross both BBB and BBTB via dopamine receptor and GRP78 receptor, and finally target glioma cells, significantly prolonging the survival time of nude mice bearing intracranial glioma. Furthermore, pHA-AOHX-VAP-DOX significantly reduced the toxicity of DOX and increased the maximum tolerated dose (MTD). Collectively, this work paves a new avenue for overcoming multiple barriers and effectively delivering chemotherapeutic agents to glioma cells while providing key evidence to identify potential receptors for glioma-targeted drug delivery."
REF00308	PDC_00308	Glioma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.32 &micro;M	&micro;M	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	.	48 h	.	MTT assay	"The coupling of peptides with chemotherapeutic drugs often increased the solubility of the drugs, so the solubility of peptide-drug conjugates was determined, and the results were shown in Fig. S9. DOX free base exhibited poor solubility, with a solubility of approximately 0.22 &plusmn; 0.03 mg/mL in PBS. However, upon formation of a peptide-drug conjugate, the hydrophilicity of the peptide significantly enhanced the solubility of DOX. The solubility of pHA-AHX-VAP-DOX and pHA-AOHX-VAP-DOX drastically increased to 7.09 &plusmn; 0.15 mg/mL and 17.29 &plusmn; 0.43 mg/mL, which was 32-fold and 78-fold higher than that of the DOX free base, respectively. The improved solubility performance was consistent with their LogP values predicted by the ALOGPS 2.1 program."	"The existence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) greatly limits the application of chemotherapy in glioma. To address this challenge, an optimal drug delivery system must efficiently cross the BBB/BBTB and specifically deliver therapeutic drugs into glioma cells while minimizing systemic toxicity. Here we demonstrated that glucose-regulated protein 78 (GRP78) and dopamine receptor D2 were highly expressed in patient-derived glioma tissues, and dopamine receptors were highly expressed on the BBB. Subsequently, we synthesized a novel Y-shaped peptide and compared the effects of different linkers on the receptor affinity and targeting ability of the peptide. A peptide-drug conjugate (pHA-AOHX-VAP-doxorubicin conjugate, pHA-AOHX-VAP-DOX) with a better affinity for glioma cells and higher solubility was derived for glioma treatment. pHA-AOHX-VAP-DOX could cross both BBB and BBTB via dopamine receptor and GRP78 receptor, and finally target glioma cells, significantly prolonging the survival time of nude mice bearing intracranial glioma. Furthermore, pHA-AOHX-VAP-DOX significantly reduced the toxicity of DOX and increased the maximum tolerated dose (MTD). Collectively, this work paves a new avenue for overcoming multiple barriers and effectively delivering chemotherapeutic agents to glioma cells while providing key evidence to identify potential receptors for glioma-targeted drug delivery."
REF00308	PDC_00307	Glioma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.62 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U87 cell	.	.	48 h	.	MTT assay	"The coupling of peptides with chemotherapeutic drugs often increased the solubility of the drugs, so the solubility of peptide-drug conjugates was determined, and the results were shown in Fig. S9. DOX free base exhibited poor solubility, with a solubility of approximately 0.22 &plusmn; 0.03 mg/mL in PBS. However, upon formation of a peptide-drug conjugate, the hydrophilicity of the peptide significantly enhanced the solubility of DOX. The solubility of pHA-AHX-VAP-DOX and pHA-AOHX-VAP-DOX drastically increased to 7.09 &plusmn; 0.15 mg/mL and 17.29 &plusmn; 0.43 mg/mL, which was 32-fold and 78-fold higher than that of the DOX free base, respectively. The improved solubility performance was consistent with their LogP values predicted by the ALOGPS 2.1 program."	"The existence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) greatly limits the application of chemotherapy in glioma. To address this challenge, an optimal drug delivery system must efficiently cross the BBB/BBTB and specifically deliver therapeutic drugs into glioma cells while minimizing systemic toxicity. Here we demonstrated that glucose-regulated protein 78 (GRP78) and dopamine receptor D2 were highly expressed in patient-derived glioma tissues, and dopamine receptors were highly expressed on the BBB. Subsequently, we synthesized a novel Y-shaped peptide and compared the effects of different linkers on the receptor affinity and targeting ability of the peptide. A peptide-drug conjugate (pHA-AOHX-VAP-doxorubicin conjugate, pHA-AOHX-VAP-DOX) with a better affinity for glioma cells and higher solubility was derived for glioma treatment. pHA-AOHX-VAP-DOX could cross both BBB and BBTB via dopamine receptor and GRP78 receptor, and finally target glioma cells, significantly prolonging the survival time of nude mice bearing intracranial glioma. Furthermore, pHA-AOHX-VAP-DOX significantly reduced the toxicity of DOX and increased the maximum tolerated dose (MTD). Collectively, this work paves a new avenue for overcoming multiple barriers and effectively delivering chemotherapeutic agents to glioma cells while providing key evidence to identify potential receptors for glioma-targeted drug delivery."
REF00308	PDC_00307	Glioma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.56 &micro;M	&micro;M	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	.	48 h	.	MTT assay	"The coupling of peptides with chemotherapeutic drugs often increased the solubility of the drugs, so the solubility of peptide-drug conjugates was determined, and the results were shown in Fig. S9. DOX free base exhibited poor solubility, with a solubility of approximately 0.22 &plusmn; 0.03 mg/mL in PBS. However, upon formation of a peptide-drug conjugate, the hydrophilicity of the peptide significantly enhanced the solubility of DOX. The solubility of pHA-AHX-VAP-DOX and pHA-AOHX-VAP-DOX drastically increased to 7.09 &plusmn; 0.15 mg/mL and 17.29 &plusmn; 0.43 mg/mL, which was 32-fold and 78-fold higher than that of the DOX free base, respectively. The improved solubility performance was consistent with their LogP values predicted by the ALOGPS 2.1 program."	"The existence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) greatly limits the application of chemotherapy in glioma. To address this challenge, an optimal drug delivery system must efficiently cross the BBB/BBTB and specifically deliver therapeutic drugs into glioma cells while minimizing systemic toxicity. Here we demonstrated that glucose-regulated protein 78 (GRP78) and dopamine receptor D2 were highly expressed in patient-derived glioma tissues, and dopamine receptors were highly expressed on the BBB. Subsequently, we synthesized a novel Y-shaped peptide and compared the effects of different linkers on the receptor affinity and targeting ability of the peptide. A peptide-drug conjugate (pHA-AOHX-VAP-doxorubicin conjugate, pHA-AOHX-VAP-DOX) with a better affinity for glioma cells and higher solubility was derived for glioma treatment. pHA-AOHX-VAP-DOX could cross both BBB and BBTB via dopamine receptor and GRP78 receptor, and finally target glioma cells, significantly prolonging the survival time of nude mice bearing intracranial glioma. Furthermore, pHA-AOHX-VAP-DOX significantly reduced the toxicity of DOX and increased the maximum tolerated dose (MTD). Collectively, this work paves a new avenue for overcoming multiple barriers and effectively delivering chemotherapeutic agents to glioma cells while providing key evidence to identify potential receptors for glioma-targeted drug delivery."
REF00306	PDC_00327	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	24 nM	nM	.	.	.	.	Pancreatic ductal adenocarcinoma	Pancreatic ductal adenocarcinoma cell TB32043mb6s2	.	.	48 h	.	WST-1 assay	"The relative specificity of SG3299 for v6, and the in vitro cytotoxic effect of SG3299 on v6-expressing murine cancer cells was confirmed with a growth inhibition assay performed on TB32043mb6s2 and TB32043 cells (high & negative v6 expression respectively). Cell viability was evaluated with a WST-1 assay following treatment with 0-105 nM of SG3299 or SG3511. The IC50 of v6-targeted SG3299 in TB32043mb6s2 was over 15-fold lower than in TB32043 cells (24 nM vs 418 nM, p < 0.001). There was no significant difference in the IC50 values for the non-targeted SG3511 between TB32043mb6s2 and TB32043 cells (223 vs 300 nM, p = 0.17)."	"The integrin v&beta;6 is expressed on &tilde;85% of pancreatic cancers with minimal expression in healthy tissues, and thus is a valid therapeutic target. We previously developed the A20FMDV2 peptide that binds with high-affinity to v&beta;6. SG3299 is a peptide-toxin conjugate that conjugates A20FMDV2 to a synthetic pyrrolobenzodiazepine (PBD) dimer cytotoxic warhead with a cathepsin B-cleavable valine-alanine linker. We have shown that SG3299 is highly effective in subcutaneous pancreatic cancer xenografts in immunodeficient models, with prolonged survival and tumour eliminations."
REF00306	PDC_00327	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	418 nM	nM	.	.	.	.	Pancreatic ductal adenocarcinoma	Pancreatic ductal adenocarcinoma cell TB32043	.	.	48 h	.	WST-1 assay	"The relative specificity of SG3299 for v6, and the in vitro cytotoxic effect of SG3299 on v6-expressing murine cancer cells was confirmed with a growth inhibition assay performed on TB32043mb6s2 and TB32043 cells (high & negative v6 expression respectively). Cell viability was evaluated with a WST-1 assay following treatment with 0-105 nM of SG3299 or SG3511. The IC50 of v6-targeted SG3299 in TB32043mb6s2 was over 15-fold lower than in TB32043 cells (24 nM vs 418 nM, p < 0.001). There was no significant difference in the IC50 values for the non-targeted SG3511 between TB32043mb6s2 and TB32043 cells (223 vs 300 nM, p = 0.17)."	"The integrin v&beta;6 is expressed on &tilde;85% of pancreatic cancers with minimal expression in healthy tissues, and thus is a valid therapeutic target. We previously developed the A20FMDV2 peptide that binds with high-affinity to v&beta;6. SG3299 is a peptide-toxin conjugate that conjugates A20FMDV2 to a synthetic pyrrolobenzodiazepine (PBD) dimer cytotoxic warhead with a cathepsin B-cleavable valine-alanine linker. We have shown that SG3299 is highly effective in subcutaneous pancreatic cancer xenografts in immunodeficient models, with prolonged survival and tumour eliminations."
REF00306	PDC_00329	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	223 nM	nM	.	.	.	.	Pancreatic ductal adenocarcinoma	Pancreatic ductal adenocarcinoma cell TB32043mb6s2	.	.	48 h	.	WST-1 assay	"The relative specificity of SG3299 for v6, and the in vitro cytotoxic effect of SG3299 on v6-expressing murine cancer cells was confirmed with a growth inhibition assay performed on TB32043mb6s2 and TB32043 cells (high & negative v6 expression respectively). Cell viability was evaluated with a WST-1 assay following treatment with 0-105 nM of SG3299 or SG3511. The IC50 of v6-targeted SG3299 in TB32043mb6s2 was over 15-fold lower than in TB32043 cells (24 nM vs 418 nM, p < 0.001). There was no significant difference in the IC50 values for the non-targeted SG3511 between TB32043mb6s2 and TB32043 cells (223 vs 300 nM, p = 0.17)."	"The integrin v&beta;6 is expressed on &tilde;85% of pancreatic cancers with minimal expression in healthy tissues, and thus is a valid therapeutic target. We previously developed the A20FMDV2 peptide that binds with high-affinity to v&beta;6. SG3299 is a peptide-toxin conjugate that conjugates A20FMDV2 to a synthetic pyrrolobenzodiazepine (PBD) dimer cytotoxic warhead with a cathepsin B-cleavable valine-alanine linker. We have shown that SG3299 is highly effective in subcutaneous pancreatic cancer xenografts in immunodeficient models, with prolonged survival and tumour eliminations."
REF00306	PDC_00329	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	300 nM	nM	.	.	.	.	Pancreatic ductal adenocarcinoma	Pancreatic ductal adenocarcinoma cell TB32043	.	.	48 h	.	WST-1 assay	"The relative specificity of SG3299 for v6, and the in vitro cytotoxic effect of SG3299 on v6-expressing murine cancer cells was confirmed with a growth inhibition assay performed on TB32043mb6s2 and TB32043 cells (high & negative v6 expression respectively). Cell viability was evaluated with a WST-1 assay following treatment with 0-105 nM of SG3299 or SG3511. The IC50 of v6-targeted SG3299 in TB32043mb6s2 was over 15-fold lower than in TB32043 cells (24 nM vs 418 nM, p < 0.001). There was no significant difference in the IC50 values for the non-targeted SG3511 between TB32043mb6s2 and TB32043 cells (223 vs 300 nM, p = 0.17)."	"The integrin v&beta;6 is expressed on &tilde;85% of pancreatic cancers with minimal expression in healthy tissues, and thus is a valid therapeutic target. We previously developed the A20FMDV2 peptide that binds with high-affinity to v&beta;6. SG3299 is a peptide-toxin conjugate that conjugates A20FMDV2 to a synthetic pyrrolobenzodiazepine (PBD) dimer cytotoxic warhead with a cathepsin B-cleavable valine-alanine linker. We have shown that SG3299 is highly effective in subcutaneous pancreatic cancer xenografts in immunodeficient models, with prolonged survival and tumour eliminations."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	92.90%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event rate	85.70%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	35.70%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	21.40%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	71.40%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	21.40%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	7.10%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	92.90%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Melflufen-related adverse event rate	92.90%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	71.40%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Neutropenia	64.30%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Anemia	64.30%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Pneumonia	21.40%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Pyrexia	14.30%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Arthralgia	7.10%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Back pain	14.30%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Fatigue	7.10%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Leukopenia	14.30%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Bone pain	14.30%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	C-reactive protein increase	14.30%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Rash	14.30%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Respiratory tract infection	14.30%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"Overall, at least one TEAE was reported in 13 (92.9%) and 13 (100.0%) patients in Arms A and B, respectively (Table 3). During cycle 1, 9 patients (64.3%) and 12 patients (92.3%), respectively, had at least one TEAE. Cumulatively, grade 3 or 4 AEs occurred in 12 (85.7%) and 12 (92.3%) patients, respectively, and serious AEs were reported in 5 (35.7%) and 9 (69.2%) patients, respectively. The most common any-grade AEs in Arms A and B, respectively, were thrombocytopenia (10 [71.4%]; 10 [76.9%]), neutropenia (9 [64.3%]; 9 [69.2%]), and anemia (9 [64.3%]; 7 [53.8%]). No phlebitis or local-infusion-related reactions were reported based on pre- and post-infusion inspection of the IV site, and there were no extravasations observed in Arm A or B. Similarly, VIP scores collected on Day 1 post-infusion and on Day 8 indicated that patients had healthy IV sites (VIP score of 0) with no signs of phlebitis following PVC administration of melflufen. The most common non-hematological AE was positive SARS-CoV-2 test (Arm A: 2 [14.3%]; Arm B: 4 [30.8%]). Pneumonia was the most common serious AE (Arm A: 2 [14.3%]; Arm B: 2 [15.4%]). The most common AE considered related to melflufen and/or dexamethasone by investigators was thrombocytopenia (Arm A: 10 [71.4%]; Arm B: 10 [76.9%]). AEs led to treatment discontinuation in 3 (21.4%) and 6 (46.2%) patients in Arms A and B, respectively."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	7.10%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"In Arm A, 4 of the 14 patients achieved an overall response (ORR 28.6% [95% CI: 8.4-58.1]) including 1 patient with CR, and the CBR was 57.1% (95% CI: 28.9-82.3). In Arm B, 1 of the 13 patients achieved an overall response (ORR 7.7% [95% CI: 0.2-36.0]), consisting of a PR, and the CBR was 15.4% (95% CI: 1.9-45.4). In the overall study population, 5 patients had an overall response (ORR 18.5% [95% CI: 6.3-38.1]). DOR data were insufficient to evaluate due to early termination of the study, the low number of patient events (1 in Arm A, 0 in Arm B), and the limited number of responses. Based on the 5 patients who had a response of PR or better at study termination (4 in Arm A, 1 in Arm B), the median TTR was 2.4 months in Arm A, 5.1 months in Arm B, and 2.6 months overall. Based on the 8 and 5 progression events in Arm A and Arm B, respectively, the median TTP was 5.8 months and 4.8 months, respectively, with a median TTP of 5.8 months in the overall population. The median PFS was 5.2 months (95% CI: 2.7 to not evaluable) and 2.9 months (95% CI: 1.5-4.6) in Arms A and B, respectively. For the overall study population, median PFS was 3.7 months (95% CI: 2.7-5.8)."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	21.40%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"In Arm A, 4 of the 14 patients achieved an overall response (ORR 28.6% [95% CI: 8.4-58.1]) including 1 patient with CR, and the CBR was 57.1% (95% CI: 28.9-82.3). In Arm B, 1 of the 13 patients achieved an overall response (ORR 7.7% [95% CI: 0.2-36.0]), consisting of a PR, and the CBR was 15.4% (95% CI: 1.9-45.4). In the overall study population, 5 patients had an overall response (ORR 18.5% [95% CI: 6.3-38.1]). DOR data were insufficient to evaluate due to early termination of the study, the low number of patient events (1 in Arm A, 0 in Arm B), and the limited number of responses. Based on the 5 patients who had a response of PR or better at study termination (4 in Arm A, 1 in Arm B), the median TTR was 2.4 months in Arm A, 5.1 months in Arm B, and 2.6 months overall. Based on the 8 and 5 progression events in Arm A and Arm B, respectively, the median TTP was 5.8 months and 4.8 months, respectively, with a median TTP of 5.8 months in the overall population. The median PFS was 5.2 months (95% CI: 2.7 to not evaluable) and 2.9 months (95% CI: 1.5-4.6) in Arms A and B, respectively. For the overall study population, median PFS was 3.7 months (95% CI: 2.7-5.8)."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	28.60%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"In Arm A, 4 of the 14 patients achieved an overall response (ORR 28.6% [95% CI: 8.4-58.1]) including 1 patient with CR, and the CBR was 57.1% (95% CI: 28.9-82.3). In Arm B, 1 of the 13 patients achieved an overall response (ORR 7.7% [95% CI: 0.2-36.0]), consisting of a PR, and the CBR was 15.4% (95% CI: 1.9-45.4). In the overall study population, 5 patients had an overall response (ORR 18.5% [95% CI: 6.3-38.1]). DOR data were insufficient to evaluate due to early termination of the study, the low number of patient events (1 in Arm A, 0 in Arm B), and the limited number of responses. Based on the 5 patients who had a response of PR or better at study termination (4 in Arm A, 1 in Arm B), the median TTR was 2.4 months in Arm A, 5.1 months in Arm B, and 2.6 months overall. Based on the 8 and 5 progression events in Arm A and Arm B, respectively, the median TTP was 5.8 months and 4.8 months, respectively, with a median TTP of 5.8 months in the overall population. The median PFS was 5.2 months (95% CI: 2.7 to not evaluable) and 2.9 months (95% CI: 1.5-4.6) in Arms A and B, respectively. For the overall study population, median PFS was 3.7 months (95% CI: 2.7-5.8)."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	14.30%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"In Arm A, 4 of the 14 patients achieved an overall response (ORR 28.6% [95% CI: 8.4-58.1]) including 1 patient with CR, and the CBR was 57.1% (95% CI: 28.9-82.3). In Arm B, 1 of the 13 patients achieved an overall response (ORR 7.7% [95% CI: 0.2-36.0]), consisting of a PR, and the CBR was 15.4% (95% CI: 1.9-45.4). In the overall study population, 5 patients had an overall response (ORR 18.5% [95% CI: 6.3-38.1]). DOR data were insufficient to evaluate due to early termination of the study, the low number of patient events (1 in Arm A, 0 in Arm B), and the limited number of responses. Based on the 5 patients who had a response of PR or better at study termination (4 in Arm A, 1 in Arm B), the median TTR was 2.4 months in Arm A, 5.1 months in Arm B, and 2.6 months overall. Based on the 8 and 5 progression events in Arm A and Arm B, respectively, the median TTP was 5.8 months and 4.8 months, respectively, with a median TTP of 5.8 months in the overall population. The median PFS was 5.2 months (95% CI: 2.7 to not evaluable) and 2.9 months (95% CI: 1.5-4.6) in Arms A and B, respectively. For the overall study population, median PFS was 3.7 months (95% CI: 2.7-5.8)."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	14.30%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"In Arm A, 4 of the 14 patients achieved an overall response (ORR 28.6% [95% CI: 8.4-58.1]) including 1 patient with CR, and the CBR was 57.1% (95% CI: 28.9-82.3). In Arm B, 1 of the 13 patients achieved an overall response (ORR 7.7% [95% CI: 0.2-36.0]), consisting of a PR, and the CBR was 15.4% (95% CI: 1.9-45.4). In the overall study population, 5 patients had an overall response (ORR 18.5% [95% CI: 6.3-38.1]). DOR data were insufficient to evaluate due to early termination of the study, the low number of patient events (1 in Arm A, 0 in Arm B), and the limited number of responses. Based on the 5 patients who had a response of PR or better at study termination (4 in Arm A, 1 in Arm B), the median TTR was 2.4 months in Arm A, 5.1 months in Arm B, and 2.6 months overall. Based on the 8 and 5 progression events in Arm A and Arm B, respectively, the median TTP was 5.8 months and 4.8 months, respectively, with a median TTP of 5.8 months in the overall population. The median PFS was 5.2 months (95% CI: 2.7 to not evaluable) and 2.9 months (95% CI: 1.5-4.6) in Arms A and B, respectively. For the overall study population, median PFS was 3.7 months (95% CI: 2.7-5.8)."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	28.60%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"In Arm A, 4 of the 14 patients achieved an overall response (ORR 28.6% [95% CI: 8.4-58.1]) including 1 patient with CR, and the CBR was 57.1% (95% CI: 28.9-82.3). In Arm B, 1 of the 13 patients achieved an overall response (ORR 7.7% [95% CI: 0.2-36.0]), consisting of a PR, and the CBR was 15.4% (95% CI: 1.9-45.4). In the overall study population, 5 patients had an overall response (ORR 18.5% [95% CI: 6.3-38.1]). DOR data were insufficient to evaluate due to early termination of the study, the low number of patient events (1 in Arm A, 0 in Arm B), and the limited number of responses. Based on the 5 patients who had a response of PR or better at study termination (4 in Arm A, 1 in Arm B), the median TTR was 2.4 months in Arm A, 5.1 months in Arm B, and 2.6 months overall. Based on the 8 and 5 progression events in Arm A and Arm B, respectively, the median TTP was 5.8 months and 4.8 months, respectively, with a median TTP of 5.8 months in the overall population. The median PFS was 5.2 months (95% CI: 2.7 to not evaluable) and 2.9 months (95% CI: 1.5-4.6) in Arms A and B, respectively. For the overall study population, median PFS was 3.7 months (95% CI: 2.7-5.8)."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00305	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Clinical benefit rate (CBR)	57.10%	%	NCT04412707	"This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy."	Phase 2	14 patients with relapsed refractory multiple myeloma.	.	.	75.6 h	.	28-day cycle	40 mg	.	"In Arm A, 4 of the 14 patients achieved an overall response (ORR 28.6% [95% CI: 8.4-58.1]) including 1 patient with CR, and the CBR was 57.1% (95% CI: 28.9-82.3). In Arm B, 1 of the 13 patients achieved an overall response (ORR 7.7% [95% CI: 0.2-36.0]), consisting of a PR, and the CBR was 15.4% (95% CI: 1.9-45.4). In the overall study population, 5 patients had an overall response (ORR 18.5% [95% CI: 6.3-38.1]). DOR data were insufficient to evaluate due to early termination of the study, the low number of patient events (1 in Arm A, 0 in Arm B), and the limited number of responses. Based on the 5 patients who had a response of PR or better at study termination (4 in Arm A, 1 in Arm B), the median TTR was 2.4 months in Arm A, 5.1 months in Arm B, and 2.6 months overall. Based on the 8 and 5 progression events in Arm A and Arm B, respectively, the median TTP was 5.8 months and 4.8 months, respectively, with a median TTP of 5.8 months in the overall population. The median PFS was 5.2 months (95% CI: 2.7 to not evaluable) and 2.9 months (95% CI: 1.5-4.6) in Arms A and B, respectively. For the overall study population, median PFS was 3.7 months (95% CI: 2.7-5.8)."	"Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that utilizes increased peptidase expression to selectively release potent alkylating agents inside tumor cells. Melflufen is hydrolyzed by peptidases and esterases to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. The high lipophilicity of melflufen facilitates passive diffusion across cell membranes. The activity and tolerability of melflufen in relapsed/refractory multiple myeloma (RRMM) were demonstrated in the O-12-M1 (NCT01897714), OCEAN (NCT03151811), and HORIZON (NCT02963493) trials."
REF00303	PDC_00349	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.38 nM	nM	.	.	.	.	Cutaneous melanoma	SORT1-positive SKMEL28 cell	.	.	72 h	.	MTT assay	"SORT1-positive SK-MEL-28 and B16-F10 melanoma cells were selected for testing the anti-proliferative effect of docetaxel and TH1902. When TH1902 biological effects were monitored, the half-maximal inhibitory concentration (IC50) of TH1902 was similar to that of docetaxel, averaging 0.38 vs. 0.39 nM, respectively, in human SK-MEL-28 cells, and 2.57 vs. 1.72 nM in murine B16-F10 cells."	"The cancer phenotype is commonly associated with aberrant glycosylation patterns. One glycan that is directly linked to cancer is the Thomsen-Friedenreich antigen (TF or CD176). It is a disaccharide composed of a galactose &beta;1-3 N-acetylgalactosamine, O-linked to a glycoprotein through serine or threonine residues and commonly written as Gal&beta;1-3GalNAc--O-Ser/Thr. The TF is therapeutically attractive due to its cryptic nature in normal cells and exposure in embryonic and cancer cells. The expression of the TF has been demonstrated in 90% of primary human carcinomas, including in the lung, the breast, and the pancreas. Additionally, cancer initiating cells or cancer stem cells in the lung, liver, and colon express the TF. The peptide sequence HGRFILPWWYAFSPS (TF-peptide) is known to bind tightly to the TF (Kd = 1.2 M) and has been demonstrated to inhibit processes directly involved in TF accessibility."
REF00303	PDC_00349	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.57 nM	nM	.	.	.	.	Mouse melanoma	SORT1-positive B16-F10 cell	.	.	72 h	.	MTT assay	"SORT1-positive SK-MEL-28 and B16-F10 melanoma cells were selected for testing the anti-proliferative effect of docetaxel and TH1902. When TH1902 biological effects were monitored, the half-maximal inhibitory concentration (IC50) of TH1902 was similar to that of docetaxel, averaging 0.38 vs. 0.39 nM, respectively, in human SK-MEL-28 cells, and 2.57 vs. 1.72 nM in murine B16-F10 cells."	"As a payload for PDCs (and ADCs), analogues of the duocarmycins are attractive. Duocarmycin SA and yatakemycin rank among the most potent natural cytotoxins discovered. The cyclopropyl and prodrug seco forms are both naturally occurring and equipotent in most circumstances. Studies of the binding-driven bonding model of their interaction with DNA suggest that their utility will be enhanced when targeted to tumor cells. In fact, SYD985, an ADC that utilizes a peptide linker for a duocarmycin analogue to trastuzumab, has recently been progressed to phase III clinical trial."
REF00303	PDC_00349	Melanoma	SORT1-positive B16-F10 cells female CD1 nude mice xenograft tumor models.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	90%	%	.	.	.	.	Mouse melanoma	SORT1-positive B16-F10 cell	.	.	12 days	35 mg/kg/wk	.	"B16-F10 melanoma syngeneic tumors were generated, with tumor sizes monitored as described in the Methods section. Tumors in xenograft-bearing, vehicle-treated mice grew at an exponential rate. Partial inhibition of tumor growth was observed after IV administration of 15 mg/kg/wk docetaxel, whereas treatment with a docetaxel-equivalent quantity of TH1902 (35 mg/kg/wk) induced tumor regression after two treatments over the period measured. Due to rapid tumor growth, only two administrations of the test articles could be performed on a weekly schedule. B16-F10 melanoma tumors from the mice treated with either vehicle, docetaxel, or TH1902 were then excised, fixed in formalin, and immunohistochemically examined."	"The efficacy of current chemotherapeutic treatments against most solid tumors is limited by their systemic toxicity, which is partly associated with the cytotoxic properties of agents such as docetaxel or doxorubicin. To avoid or minimize adverse effects from chemotherapeutic molecules, a promising targeted approach is through peptide-drug conjugates (PDCs) that link anticancer molecules to peptides designed to interact with receptors highly expressed on cancer cells, and which can mediate the molecules rapid internalization within those cells. One such receptor is sortilin (SORT1), also known as neurotensin receptor3, a membranebound receptor that belongs to the VPS10P family of receptors. TH19P01 peptide was recently designed to target and exploit SORT1s ligand internalization function. Studies have confirmed that both TH1902 (a docetaxel-TH19P01 conjugate) and TH1904 (a doxorubicin-TH19P01 conjugate) require a SORT1-dependent mechanism of action to exert anticancer activities. In recent preclinical studies performed in immunocompromised animal models, which are unable to produce mature T-cells, TH1902 was effective against several human SORT1-positive xenograft models including triple-negative breast cancer (TNBC), ovarian cancer, and endometrial cancer."
REF00302	PDC_00313	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell survival rate	12%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	24 h	20 &micro;g/mL	CCK-8 assay	"Subsequently, the cell toxicity of the DOX, DOX-SH, and PNS-SS-DOX was also investigated using the CCK-8 method. As shown in Figure8b, all three materials display significant concentration-dependent cytotoxicity. Additionally, it can be observed that at the same concentration, the cytotoxicity of DOX-SH to MCF-7 cells was nearly identical to that of DOX, indicating that thiolation did not affect the efficacy of DOX. Furthermore, the PNS-SS-DOX group exhibited stronger cytotoxicity to MCF-7 cells. Particularly, at a material concentration of 20ug mL-1, the cell survival rate for the PNS-SS-DOX group was only 12 %, while that of the DOX-SH group was 20 %. We suggest that this effect is possibly due to the modification of PNSs with DOX-SH. On one hand, the hydrophilic peptides effectively improved the solubility of the hydrophobic drug DOX-SH, and on the other hand, the positively charged PNSs enhanced the drug uptake by cancer cells, thus increasing the cancer cell killing efficacy."	"Therefore, in this study, we present an intelligent drug delivery system based on 2D PNSs, utilizing a thermosensitive chitosan (CS) hydrogel as a sustained release platform to achieve the goal of long-term and effective drug treatment in the body. Under specific conditions, the peptide denoted by the sequence of Fmoc-FKKGSHC undergoes self-assembly, forming 2D PNSs with uniform nanostructure. PNSs are then successfully covalently linked to the thiol-modified DOX via the disulfide bonds, resulting in the synthesis of a 2D PDCs (PNS-SS-DOX). Subsequently, the PNS-SS-DOX PDCs are encapsulated within the injectable CS-based thermosensitive hydrogels. To validate the feasibility of this novel intelligent responsive drug delivery system, we conduct invitro release testing using the CS hydrogels and tested the GSH-responsive release of the PNS-SS-DOX, simulating the tumor cell environment. The results of the study indicate that the hydrogels exhibited pH-responsive release and swelling, providing favorable conditions for the controlled release of the PNS-SS-DOX. Furthermore, the outstanding sustained release effect also facilitated the effective accumulation of the PNS-SS-DOX at the tumor site, reducing inflammation reactions caused by multiple dosages."
REF00302	PDC_00313	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell survival rate	32%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	24 h	15 &micro;g/mL	CCK-8 assay	"Subsequently, the cell toxicity of the DOX, DOX-SH, and PNS-SS-DOX was also investigated using the CCK-8 method. As shown in Figure8b, all three materials display significant concentration-dependent cytotoxicity. Additionally, it can be observed that at the same concentration, the cytotoxicity of DOX-SH to MCF-7 cells was nearly identical to that of DOX, indicating that thiolation did not affect the efficacy of DOX. Furthermore, the PNS-SS-DOX group exhibited stronger cytotoxicity to MCF-7 cells. Particularly, at a material concentration of 20ug mL-1, the cell survival rate for the PNS-SS-DOX group was only 12 %, while that of the DOX-SH group was 20 %. We suggest that this effect is possibly due to the modification of PNSs with DOX-SH. On one hand, the hydrophilic peptides effectively improved the solubility of the hydrophobic drug DOX-SH, and on the other hand, the positively charged PNSs enhanced the drug uptake by cancer cells, thus increasing the cancer cell killing efficacy."	"Therefore, in this study, we present an intelligent drug delivery system based on 2D PNSs, utilizing a thermosensitive chitosan (CS) hydrogel as a sustained release platform to achieve the goal of long-term and effective drug treatment in the body. Under specific conditions, the peptide denoted by the sequence of Fmoc-FKKGSHC undergoes self-assembly, forming 2D PNSs with uniform nanostructure. PNSs are then successfully covalently linked to the thiol-modified DOX via the disulfide bonds, resulting in the synthesis of a 2D PDCs (PNS-SS-DOX). Subsequently, the PNS-SS-DOX PDCs are encapsulated within the injectable CS-based thermosensitive hydrogels. To validate the feasibility of this novel intelligent responsive drug delivery system, we conduct invitro release testing using the CS hydrogels and tested the GSH-responsive release of the PNS-SS-DOX, simulating the tumor cell environment. The results of the study indicate that the hydrogels exhibited pH-responsive release and swelling, providing favorable conditions for the controlled release of the PNS-SS-DOX. Furthermore, the outstanding sustained release effect also facilitated the effective accumulation of the PNS-SS-DOX at the tumor site, reducing inflammation reactions caused by multiple dosages."
REF00302	PDC_00313	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell survival rate	55%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	24 h	10 &micro;g/mL	CCK-8 assay	"Subsequently, the cell toxicity of the DOX, DOX-SH, and PNS-SS-DOX was also investigated using the CCK-8 method. As shown in Figure8b, all three materials display significant concentration-dependent cytotoxicity. Additionally, it can be observed that at the same concentration, the cytotoxicity of DOX-SH to MCF-7 cells was nearly identical to that of DOX, indicating that thiolation did not affect the efficacy of DOX. Furthermore, the PNS-SS-DOX group exhibited stronger cytotoxicity to MCF-7 cells. Particularly, at a material concentration of 20ug mL-1, the cell survival rate for the PNS-SS-DOX group was only 12 %, while that of the DOX-SH group was 20 %. We suggest that this effect is possibly due to the modification of PNSs with DOX-SH. On one hand, the hydrophilic peptides effectively improved the solubility of the hydrophobic drug DOX-SH, and on the other hand, the positively charged PNSs enhanced the drug uptake by cancer cells, thus increasing the cancer cell killing efficacy."	"Therefore, in this study, we present an intelligent drug delivery system based on 2D PNSs, utilizing a thermosensitive chitosan (CS) hydrogel as a sustained release platform to achieve the goal of long-term and effective drug treatment in the body. Under specific conditions, the peptide denoted by the sequence of Fmoc-FKKGSHC undergoes self-assembly, forming 2D PNSs with uniform nanostructure. PNSs are then successfully covalently linked to the thiol-modified DOX via the disulfide bonds, resulting in the synthesis of a 2D PDCs (PNS-SS-DOX). Subsequently, the PNS-SS-DOX PDCs are encapsulated within the injectable CS-based thermosensitive hydrogels. To validate the feasibility of this novel intelligent responsive drug delivery system, we conduct invitro release testing using the CS hydrogels and tested the GSH-responsive release of the PNS-SS-DOX, simulating the tumor cell environment. The results of the study indicate that the hydrogels exhibited pH-responsive release and swelling, providing favorable conditions for the controlled release of the PNS-SS-DOX. Furthermore, the outstanding sustained release effect also facilitated the effective accumulation of the PNS-SS-DOX at the tumor site, reducing inflammation reactions caused by multiple dosages."
REF00302	PDC_00313	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell survival rate	75%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	24 h	5 &micro;g/mL	CCK-8 assay	"Subsequently, the cell toxicity of the DOX, DOX-SH, and PNS-SS-DOX was also investigated using the CCK-8 method. As shown in Figure8b, all three materials display significant concentration-dependent cytotoxicity. Additionally, it can be observed that at the same concentration, the cytotoxicity of DOX-SH to MCF-7 cells was nearly identical to that of DOX, indicating that thiolation did not affect the efficacy of DOX. Furthermore, the PNS-SS-DOX group exhibited stronger cytotoxicity to MCF-7 cells. Particularly, at a material concentration of 20ug mL-1, the cell survival rate for the PNS-SS-DOX group was only 12 %, while that of the DOX-SH group was 20 %. We suggest that this effect is possibly due to the modification of PNSs with DOX-SH. On one hand, the hydrophilic peptides effectively improved the solubility of the hydrophobic drug DOX-SH, and on the other hand, the positively charged PNSs enhanced the drug uptake by cancer cells, thus increasing the cancer cell killing efficacy."	"Therefore, in this study, we present an intelligent drug delivery system based on 2D PNSs, utilizing a thermosensitive chitosan (CS) hydrogel as a sustained release platform to achieve the goal of long-term and effective drug treatment in the body. Under specific conditions, the peptide denoted by the sequence of Fmoc-FKKGSHC undergoes self-assembly, forming 2D PNSs with uniform nanostructure. PNSs are then successfully covalently linked to the thiol-modified DOX via the disulfide bonds, resulting in the synthesis of a 2D PDCs (PNS-SS-DOX). Subsequently, the PNS-SS-DOX PDCs are encapsulated within the injectable CS-based thermosensitive hydrogels. To validate the feasibility of this novel intelligent responsive drug delivery system, we conduct invitro release testing using the CS hydrogels and tested the GSH-responsive release of the PNS-SS-DOX, simulating the tumor cell environment. The results of the study indicate that the hydrogels exhibited pH-responsive release and swelling, providing favorable conditions for the controlled release of the PNS-SS-DOX. Furthermore, the outstanding sustained release effect also facilitated the effective accumulation of the PNS-SS-DOX at the tumor site, reducing inflammation reactions caused by multiple dosages."
REF00301	PDC_00350	Psoriasis-like inflammation	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	23.31 &micro;M	&micro;M	.	.	.	.	Normal	HaCaT cell	.	.	.	.	PDE Activity Colorimetric Assay	"To confirm that TM5, chemically combined with SDT7, conserves the PDE4 inhibition properties of PAR, we evaluated its dose-dependent effect using a PDE Activity Colorimetric Assay Kit. This assay relies on the principle that PDEs catalyze the hydrolysis of cyclic nucleotides, resulting in the production of nucleosides and phosphates. The concentration of 5-AMP, a product of this reaction, was measured to assess PDE activity. TM5 exhibited an IC50 of 23.31 &mu;m, indicating its ability to inhibit PDE enzymatic activity at micromolar concentrations."	"In this study, physicochemical criteria based on cell-penetrating peptides are employed to design transcellular peptides derived from an antimicrobial peptides library. Among the statistically designed transcellular peptides (SDTs), SDT7 exhibits higher skin permeability, faster kinetics, and improved cell permeability in human keratinocyte cells compared to the control peptide. Subsequently, it is found that 6-Paradol (PAR) exhibits inhibitory activity against phosphodiesterase 4, which can be utilized for an anti-inflammatory PDC."
REF00300	PDC_00082	Melanoma	.	Revealed Based on the Cell Line Data	.	Cell survival rate	88%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	72 h	0.625 &micro;M	MTT assay	"Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus."	"In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics."
REF00300	PDC_00083	Melanoma	.	Revealed Based on the Cell Line Data	.	Cell survival rate	94%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	72 h	0.625 &micro;M	MTT assay	"Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus."	"In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics."
REF00300	PDC_00082	Melanoma	.	Revealed Based on the Cell Line Data	.	Cell survival rate	72%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	72 h	1.25 &micro;M	MTT assay	"Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus."	"In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics."
REF00300	PDC_00083	Melanoma	.	Revealed Based on the Cell Line Data	.	Cell survival rate	86%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	72 h	1.25 &micro;M	MTT assay	"Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus."	"In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics."
REF00300	PDC_00082	Melanoma	.	Revealed Based on the Cell Line Data	.	Cell survival rate	62%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	72 h	2.5 &micro;M	MTT assay	"Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus."	"In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics."
REF00300	PDC_00083	Melanoma	.	Revealed Based on the Cell Line Data	.	Cell survival rate	74%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	72 h	2.5 &micro;M	MTT assay	"Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus."	"In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics."
REF00300	PDC_00082	Melanoma	.	Revealed Based on the Cell Line Data	.	Cell survival rate	60%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	72 h	5 &micro;M	MTT assay	"Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus."	"In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics."
REF00300	PDC_00083	Melanoma	.	Revealed Based on the Cell Line Data	.	Cell survival rate	57%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	72 h	5 &micro;M	MTT assay	"Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus."	"In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics."
REF00300	PDC_00082	Melanoma	.	Revealed Based on the Cell Line Data	.	Cell survival rate	43%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	72 h	10 &micro;M	MTT assay	"Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus."	"In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics."
REF00300	PDC_00083	Melanoma	.	Revealed Based on the Cell Line Data	.	Cell survival rate	55%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	72 h	10 &micro;M	MTT assay	"Subsequently, the cytotoxicity of these conjugates against B16-F10 cells was determined. As shown in Fig. 4B, CPT-AAM-1 and CPT-AAM-2 displayed significant pH-dependent antitumor activity after 72 h of treatment, whereas the cytotoxicity of CPT showed no obvious difference at pH 7.4 and 5.5. Notably, CPT-AAM-1 and CPT-AAM-2 exhibited greater cytotoxicity than free CPT under acidic conditions, particularly at high concentrations. Compared to CPT-AAM-2, CPT-AAM-1 displayed strong antitumor activity, suggesting that AAM-1 could deliver more CPT molecules into cells. In addition, this result further demonstrates that the C-terminus of AAM is more suitable for drug conjugation than the N-terminus."	"In this study, we developed novel melittin analogs with pH-responsive cell-penetrating and membrane-lytic activities by replacing arginines and lysines with histidines. Importantly, we found that the conjugation of cargoes to the N-terminus of melittin analogs decreased their cell-penetrating and membrane-lytic activity compared to the C-terminus, implying that the C-terminus of analogs is more suitable for cargo conjugation. After the attachment of CPT, CPT-AAM-1 and CPT-AAM-2 displayed obvious pH-responsive antitumor activity. CPT-AAM-1 and CPT-AAM-2 destroyed tumor cells through the release of CPT and membrane disruption. Compared with CPT-AAM-2, CPT-AAM-1 showed stronger antitumor activity under acidic conditions. Notably, CPT-AAM-1 significantly inhibited the tumor growth in vivo compared with AAM, AAM-1, and CPT. In addition, CPT-AAM-1 showed relatively low toxicity compared with melittin and CPT. Taken together, our results demonstrate that CPT-AAM-1, with efficient pH-responsive cell-penetrating and membrane-lytic activities, possesses significant therapeutic potential for tumor therapy. This study provides a novel strategy for the development of PDCs based on pH-responsive AMPs for oncology therapeutics."
REF00299	PDC_00253	Pancreatic ductal adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	17.63 &plusmn; 2.334 nM	nM	.	.	.	.	Pancreatic ductal adenocarcinoma	MIA PaCa-2 cell	.	.	72 h	.	MTT assay	"The tested compounds cytotoxic activity was determined using the MTT test, which is based on the ability to convert tetrazole salts to water insoluble formazan through mitochondrial dehydrogenases. Our results show a high cytotoxic effect on all pancreatic cancer cell lines. Exposing pancreatic cell lines MIA PaCa-2 and AsPC-1 to OGF-Gem decreased viability. Importantly, the OGF-Gem conjugate demonstrated a more pronounced cytotoxic effect against the metastatic pancreatic cancer cell line AsPC-1 compared to the commonly used chemotherapeutic agent. The results obtained for non-tumor-transformed cellsa human embryonic kidney line HEK-293 and human primary dermal fibroblast line HDFa presented a slight cytotoxicity effect from the OGF-Gem derivative within 3 days of incubation for all tested concentrations. Interestingly, an 80% reduction in HEK-293 cell viability was observed for the 100 nM Gem compared to the 100 nM OGF-Gem derivative. In HDFa cells, 100 nM Gem reduced viability to 35%, while the OGF-Gem conjugate slightly decreased the viability (to 75% viability) after 72 h of incubation. Based on the analysis of the results, concentrations of 3.125, 12.5, 50, and 100 nM, as well as an incubation time of 72 h, were selected for further experiments on the three pancreatic cancer cell lines."	"Therefore, we designed, synthesized, and characterized an OGF-Gem conjugate, where OGF and Gem are tethered by an organic linker (Figure 1). Gem was subjected to selective protection using the tert-butoxycarbonyl (Boc) group and prepared as gemcitabine hemisuccinate. 5-O-diBoc-gemcitabine hemisuccinate was conjugated with the OGF peptide in solution. We demonstrated the cytotoxic activity of the OGF-Gem conjugate against pancreatic cancer cell lines, including the metastatic line (MIA PaCa-2 and AsPC-1). Furthermore, we confirmed that OGF-Gem is either not cytotoxic or significantly less cytotoxic to two non-tumor-transformed human cellskidney (HEK-293) and skin fibroblast cells (HDFa). We also determined the effect of OGF-Gem on cell cycle inhibition, and the inhibition of cell proliferation, senescent cells, and apoptosis. We have demonstrated that OGF-Gem has antimetastatic potential due to inhibited pancreatic tumor cell (AsPC-1)-induced platelet aggregation. This can significantly impact the inhibition of disease progression (metastasis) of pancreatic cancer."
REF00299	PDC_00253	Pancreatic ductal adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	27.44 &plusmn; 9.161 nM	nM	.	.	.	.	Pancreatic ductal adenocarcinoma	AsPC-1 cell	.	.	72 h	.	MTT assay	"The tested compounds cytotoxic activity was determined using the MTT test, which is based on the ability to convert tetrazole salts to water insoluble formazan through mitochondrial dehydrogenases. Our results show a high cytotoxic effect on all pancreatic cancer cell lines. Exposing pancreatic cell lines MIA PaCa-2 and AsPC-1 to OGF-Gem decreased viability. Importantly, the OGF-Gem conjugate demonstrated a more pronounced cytotoxic effect against the metastatic pancreatic cancer cell line AsPC-1 compared to the commonly used chemotherapeutic agent. The results obtained for non-tumor-transformed cellsa human embryonic kidney line HEK-293 and human primary dermal fibroblast line HDFa presented a slight cytotoxicity effect from the OGF-Gem derivative within 3 days of incubation for all tested concentrations. Interestingly, an 80% reduction in HEK-293 cell viability was observed for the 100 nM Gem compared to the 100 nM OGF-Gem derivative. In HDFa cells, 100 nM Gem reduced viability to 35%, while the OGF-Gem conjugate slightly decreased the viability (to 75% viability) after 72 h of incubation. Based on the analysis of the results, concentrations of 3.125, 12.5, 50, and 100 nM, as well as an incubation time of 72 h, were selected for further experiments on the three pancreatic cancer cell lines."	"Therefore, we designed, synthesized, and characterized an OGF-Gem conjugate, where OGF and Gem are tethered by an organic linker (Figure 1). Gem was subjected to selective protection using the tert-butoxycarbonyl (Boc) group and prepared as gemcitabine hemisuccinate. 5-O-diBoc-gemcitabine hemisuccinate was conjugated with the OGF peptide in solution. We demonstrated the cytotoxic activity of the OGF-Gem conjugate against pancreatic cancer cell lines, including the metastatic line (MIA PaCa-2 and AsPC-1). Furthermore, we confirmed that OGF-Gem is either not cytotoxic or significantly less cytotoxic to two non-tumor-transformed human cellskidney (HEK-293) and skin fibroblast cells (HDFa). We also determined the effect of OGF-Gem on cell cycle inhibition, and the inhibition of cell proliferation, senescent cells, and apoptosis. We have demonstrated that OGF-Gem has antimetastatic potential due to inhibited pancreatic tumor cell (AsPC-1)-induced platelet aggregation. This can significantly impact the inhibition of disease progression (metastasis) of pancreatic cancer."
REF00296	PDC_00018	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.1 &plusmn; 0.1 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	.	.	"The main drug-related toxic side effect of anthracyclines is cardiotoxicity, leading to cardiomyopathy and heart failure. Comparative experiments to determine the cardiotoxicity of peptide-anthracycline conjugates with different linkages might be informative for the other conjugates with different types of drugs as well. For this purpose, human cardiomyocytes (HCM) and human umbilical vein endothelial cells (HUVEC) were used as models. The long-term (0-72 h) cytotoxic effect of sixteen GnRH-based conjugates containing Dox and Dau was determined by real-time impedimetric sensing using the xCELLigence SP system (ACEA Biosciences, San Diego, CA, USA) [75]. The results indicated that the ester-linked GnRH-Dox conjugates, including Zoptarelin Doxorubicin, showed significant toxicity at 100 nM and 1 uM, which was remarkably pronounced on the HCM cells. The cytotoxic effect was comparable to that of the free drug, especially at the highest concentration. In contrast, the conjugates with oxime-linked Dau showed no or only a minor toxicity on both the cell lines (Table 2). These data confirm that the linkage between the payload and homing peptide has a significant influence on early drug release and, consequently, an undesired toxic side effect. We may also conclude that the search for more suitable homing peptides might be more important than the application of cleavable bonds between the drug and the peptide to develop efficient DDSs."	"The efficacy of current chemotherapeutic treatments against most solid tumors is limited by their systemic toxicity, which is partly associated with the cytotoxic properties of agents such as docetaxel or doxorubicin. To avoid or minimize adverse effects from chemotherapeutic molecules, a promising targeted approach is through peptide-drug conjugates (PDCs) that link anticancer molecules to peptides designed to interact with receptors highly expressed on cancer cells, and which can mediate the molecules rapid internalization within those cells. One such receptor is sortilin (SORT1), also known as neurotensin receptor3, a membranebound receptor that belongs to the VPS10P family of receptors. TH19P01 peptide was recently designed to target and exploit SORT1s ligand internalization function. Studies have confirmed that both TH1902 (a docetaxel-TH19P01 conjugate) and TH1904 (a doxorubicin-TH19P01 conjugate) require a SORT1-dependent mechanism of action to exert anticancer activities. In recent preclinical studies performed in immunocompromised animal models, which are unable to produce mature T-cells, TH1902 was effective against several human SORT1-positive xenograft models including triple-negative breast cancer (TNBC), ovarian cancer, and endometrial cancer."
REF00296	PDC_00208	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	6.5 &plusmn; 1.8 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	.	.	"The main drug-related toxic side effect of anthracyclines is cardiotoxicity, leading to cardiomyopathy and heart failure. Comparative experiments to determine the cardiotoxicity of peptide-anthracycline conjugates with different linkages might be informative for the other conjugates with different types of drugs as well. For this purpose, human cardiomyocytes (HCM) and human umbilical vein endothelial cells (HUVEC) were used as models. The long-term (0-72 h) cytotoxic effect of sixteen GnRH-based conjugates containing Dox and Dau was determined by real-time impedimetric sensing using the xCELLigence SP system (ACEA Biosciences, San Diego, CA, USA) [75]. The results indicated that the ester-linked GnRH-Dox conjugates, including Zoptarelin Doxorubicin, showed significant toxicity at 100 nM and 1 uM, which was remarkably pronounced on the HCM cells. The cytotoxic effect was comparable to that of the free drug, especially at the highest concentration. In contrast, the conjugates with oxime-linked Dau showed no or only a minor toxicity on both the cell lines (Table 2). These data confirm that the linkage between the payload and homing peptide has a significant influence on early drug release and, consequently, an undesired toxic side effect. We may also conclude that the search for more suitable homing peptides might be more important than the application of cleavable bonds between the drug and the peptide to develop efficient DDSs."	"The cancer phenotype is commonly associated with aberrant glycosylation patterns. One glycan that is directly linked to cancer is the Thomsen-Friedenreich antigen (TF or CD176). It is a disaccharide composed of a galactose &beta;1-3 N-acetylgalactosamine, O-linked to a glycoprotein through serine or threonine residues and commonly written as Gal&beta;1-3GalNAc--O-Ser/Thr. The TF is therapeutically attractive due to its cryptic nature in normal cells and exposure in embryonic and cancer cells. The expression of the TF has been demonstrated in 90% of primary human carcinomas, including in the lung, the breast, and the pancreas. Additionally, cancer initiating cells or cancer stem cells in the lung, liver, and colon express the TF. The peptide sequence HGRFILPWWYAFSPS (TF-peptide) is known to bind tightly to the TF (Kd = 1.2 M) and has been demonstrated to inhibit processes directly involved in TF accessibility."
REF00296	PDC_00015	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	3.9 &plusmn; 1.2 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	.	.	"The main drug-related toxic side effect of anthracyclines is cardiotoxicity, leading to cardiomyopathy and heart failure. Comparative experiments to determine the cardiotoxicity of peptide-anthracycline conjugates with different linkages might be informative for the other conjugates with different types of drugs as well. For this purpose, human cardiomyocytes (HCM) and human umbilical vein endothelial cells (HUVEC) were used as models. The long-term (0-72 h) cytotoxic effect of sixteen GnRH-based conjugates containing Dox and Dau was determined by real-time impedimetric sensing using the xCELLigence SP system (ACEA Biosciences, San Diego, CA, USA) [75]. The results indicated that the ester-linked GnRH-Dox conjugates, including Zoptarelin Doxorubicin, showed significant toxicity at 100 nM and 1 uM, which was remarkably pronounced on the HCM cells. The cytotoxic effect was comparable to that of the free drug, especially at the highest concentration. In contrast, the conjugates with oxime-linked Dau showed no or only a minor toxicity on both the cell lines (Table 2). These data confirm that the linkage between the payload and homing peptide has a significant influence on early drug release and, consequently, an undesired toxic side effect. We may also conclude that the search for more suitable homing peptides might be more important than the application of cleavable bonds between the drug and the peptide to develop efficient DDSs."	"As a payload for PDCs (and ADCs), analogues of the duocarmycins are attractive. Duocarmycin SA and yatakemycin rank among the most potent natural cytotoxins discovered. The cyclopropyl and prodrug seco forms are both naturally occurring and equipotent in most circumstances. Studies of the binding-driven bonding model of their interaction with DNA suggest that their utility will be enhanced when targeted to tumor cells. In fact, SYD985, an ADC that utilizes a peptide linker for a duocarmycin analogue to trastuzumab, has recently been progressed to phase III clinical trial."
REF00296	PDC_00017	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.8 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	.	.	"The main drug-related toxic side effect of anthracyclines is cardiotoxicity, leading to cardiomyopathy and heart failure. Comparative experiments to determine the cardiotoxicity of peptide-anthracycline conjugates with different linkages might be informative for the other conjugates with different types of drugs as well. For this purpose, human cardiomyocytes (HCM) and human umbilical vein endothelial cells (HUVEC) were used as models. The long-term (0-72 h) cytotoxic effect of sixteen GnRH-based conjugates containing Dox and Dau was determined by real-time impedimetric sensing using the xCELLigence SP system (ACEA Biosciences, San Diego, CA, USA) [75]. The results indicated that the ester-linked GnRH-Dox conjugates, including Zoptarelin Doxorubicin, showed significant toxicity at 100 nM and 1 uM, which was remarkably pronounced on the HCM cells. The cytotoxic effect was comparable to that of the free drug, especially at the highest concentration. In contrast, the conjugates with oxime-linked Dau showed no or only a minor toxicity on both the cell lines (Table 2). These data confirm that the linkage between the payload and homing peptide has a significant influence on early drug release and, consequently, an undesired toxic side effect. We may also conclude that the search for more suitable homing peptides might be more important than the application of cleavable bonds between the drug and the peptide to develop efficient DDSs."	"As a payload for PDCs (and ADCs), analogues of the duocarmycins are attractive. Duocarmycin SA and yatakemycin rank among the most potent natural cytotoxins discovered. The cyclopropyl and prodrug seco forms are both naturally occurring and equipotent in most circumstances. Studies of the binding-driven bonding model of their interaction with DNA suggest that their utility will be enhanced when targeted to tumor cells. In fact, SYD985, an ADC that utilizes a peptide linker for a duocarmycin analogue to trastuzumab, has recently been progressed to phase III clinical trial."
REF00296	PDC_00011	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	3.1 &plusmn; 1.7 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	.	.	"The main drug-related toxic side effect of anthracyclines is cardiotoxicity, leading to cardiomyopathy and heart failure. Comparative experiments to determine the cardiotoxicity of peptide-anthracycline conjugates with different linkages might be informative for the other conjugates with different types of drugs as well. For this purpose, human cardiomyocytes (HCM) and human umbilical vein endothelial cells (HUVEC) were used as models. The long-term (0-72 h) cytotoxic effect of sixteen GnRH-based conjugates containing Dox and Dau was determined by real-time impedimetric sensing using the xCELLigence SP system (ACEA Biosciences, San Diego, CA, USA) [75]. The results indicated that the ester-linked GnRH-Dox conjugates, including Zoptarelin Doxorubicin, showed significant toxicity at 100 nM and 1 uM, which was remarkably pronounced on the HCM cells. The cytotoxic effect was comparable to that of the free drug, especially at the highest concentration. In contrast, the conjugates with oxime-linked Dau showed no or only a minor toxicity on both the cell lines (Table 2). These data confirm that the linkage between the payload and homing peptide has a significant influence on early drug release and, consequently, an undesired toxic side effect. We may also conclude that the search for more suitable homing peptides might be more important than the application of cleavable bonds between the drug and the peptide to develop efficient DDSs."	"The cancer phenotype is commonly associated with aberrant glycosylation patterns. One glycan that is directly linked to cancer is the Thomsen-Friedenreich antigen (TF or CD176). It is a disaccharide composed of a galactose &beta;1-3 N-acetylgalactosamine, O-linked to a glycoprotein through serine or threonine residues and commonly written as Gal&beta;1-3GalNAc--O-Ser/Thr. The TF is therapeutically attractive due to its cryptic nature in normal cells and exposure in embryonic and cancer cells. The expression of the TF has been demonstrated in 90% of primary human carcinomas, including in the lung, the breast, and the pancreas. Additionally, cancer initiating cells or cancer stem cells in the lung, liver, and colon express the TF. The peptide sequence HGRFILPWWYAFSPS (TF-peptide) is known to bind tightly to the TF (Kd = 1.2 M) and has been demonstrated to inhibit processes directly involved in TF accessibility."
REF00296	PDC_00013	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	2.9 &plusmn; 0.9 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	.	.	"The main drug-related toxic side effect of anthracyclines is cardiotoxicity, leading to cardiomyopathy and heart failure. Comparative experiments to determine the cardiotoxicity of peptide-anthracycline conjugates with different linkages might be informative for the other conjugates with different types of drugs as well. For this purpose, human cardiomyocytes (HCM) and human umbilical vein endothelial cells (HUVEC) were used as models. The long-term (0-72 h) cytotoxic effect of sixteen GnRH-based conjugates containing Dox and Dau was determined by real-time impedimetric sensing using the xCELLigence SP system (ACEA Biosciences, San Diego, CA, USA) [75]. The results indicated that the ester-linked GnRH-Dox conjugates, including Zoptarelin Doxorubicin, showed significant toxicity at 100 nM and 1 uM, which was remarkably pronounced on the HCM cells. The cytotoxic effect was comparable to that of the free drug, especially at the highest concentration. In contrast, the conjugates with oxime-linked Dau showed no or only a minor toxicity on both the cell lines (Table 2). These data confirm that the linkage between the payload and homing peptide has a significant influence on early drug release and, consequently, an undesired toxic side effect. We may also conclude that the search for more suitable homing peptides might be more important than the application of cleavable bonds between the drug and the peptide to develop efficient DDSs."	"As a payload for PDCs (and ADCs), analogues of the duocarmycins are attractive. Duocarmycin SA and yatakemycin rank among the most potent natural cytotoxins discovered. The cyclopropyl and prodrug seco forms are both naturally occurring and equipotent in most circumstances. Studies of the binding-driven bonding model of their interaction with DNA suggest that their utility will be enhanced when targeted to tumor cells. In fact, SYD985, an ADC that utilizes a peptide linker for a duocarmycin analogue to trastuzumab, has recently been progressed to phase III clinical trial."
REF00296	PDC_00016	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	3.0 &plusmn; 0.4 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	.	.	"The main drug-related toxic side effect of anthracyclines is cardiotoxicity, leading to cardiomyopathy and heart failure. Comparative experiments to determine the cardiotoxicity of peptide-anthracycline conjugates with different linkages might be informative for the other conjugates with different types of drugs as well. For this purpose, human cardiomyocytes (HCM) and human umbilical vein endothelial cells (HUVEC) were used as models. The long-term (0-72 h) cytotoxic effect of sixteen GnRH-based conjugates containing Dox and Dau was determined by real-time impedimetric sensing using the xCELLigence SP system (ACEA Biosciences, San Diego, CA, USA) [75]. The results indicated that the ester-linked GnRH-Dox conjugates, including Zoptarelin Doxorubicin, showed significant toxicity at 100 nM and 1 uM, which was remarkably pronounced on the HCM cells. The cytotoxic effect was comparable to that of the free drug, especially at the highest concentration. In contrast, the conjugates with oxime-linked Dau showed no or only a minor toxicity on both the cell lines (Table 2). These data confirm that the linkage between the payload and homing peptide has a significant influence on early drug release and, consequently, an undesired toxic side effect. We may also conclude that the search for more suitable homing peptides might be more important than the application of cleavable bonds between the drug and the peptide to develop efficient DDSs."	"The cancer phenotype is commonly associated with aberrant glycosylation patterns. One glycan that is directly linked to cancer is the Thomsen-Friedenreich antigen (TF or CD176). It is a disaccharide composed of a galactose &beta;1-3 N-acetylgalactosamine, O-linked to a glycoprotein through serine or threonine residues and commonly written as Gal&beta;1-3GalNAc--O-Ser/Thr. The TF is therapeutically attractive due to its cryptic nature in normal cells and exposure in embryonic and cancer cells. The expression of the TF has been demonstrated in 90% of primary human carcinomas, including in the lung, the breast, and the pancreas. Additionally, cancer initiating cells or cancer stem cells in the lung, liver, and colon express the TF. The peptide sequence HGRFILPWWYAFSPS (TF-peptide) is known to bind tightly to the TF (Kd = 1.2 M) and has been demonstrated to inhibit processes directly involved in TF accessibility."
REF00296	PDC_00018	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	2.4 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	72 h	.	.	"The main drug-related toxic side effect of anthracyclines is cardiotoxicity, leading to cardiomyopathy and heart failure. Comparative experiments to determine the cardiotoxicity of peptide-anthracycline conjugates with different linkages might be informative for the other conjugates with different types of drugs as well. For this purpose, human cardiomyocytes (HCM) and human umbilical vein endothelial cells (HUVEC) were used as models. The long-term (0-72 h) cytotoxic effect of sixteen GnRH-based conjugates containing Dox and Dau was determined by real-time impedimetric sensing using the xCELLigence SP system (ACEA Biosciences, San Diego, CA, USA) [75]. The results indicated that the ester-linked GnRH-Dox conjugates, including Zoptarelin Doxorubicin, showed significant toxicity at 100 nM and 1 uM, which was remarkably pronounced on the HCM cells. The cytotoxic effect was comparable to that of the free drug, especially at the highest concentration. In contrast, the conjugates with oxime-linked Dau showed no or only a minor toxicity on both the cell lines (Table 2). These data confirm that the linkage between the payload and homing peptide has a significant influence on early drug release and, consequently, an undesired toxic side effect. We may also conclude that the search for more suitable homing peptides might be more important than the application of cleavable bonds between the drug and the peptide to develop efficient DDSs."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00208	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	27.8 &plusmn; 4.2 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	72 h	.	.	"The main drug-related toxic side effect of anthracyclines is cardiotoxicity, leading to cardiomyopathy and heart failure. Comparative experiments to determine the cardiotoxicity of peptide-anthracycline conjugates with different linkages might be informative for the other conjugates with different types of drugs as well. For this purpose, human cardiomyocytes (HCM) and human umbilical vein endothelial cells (HUVEC) were used as models. The long-term (0-72 h) cytotoxic effect of sixteen GnRH-based conjugates containing Dox and Dau was determined by real-time impedimetric sensing using the xCELLigence SP system (ACEA Biosciences, San Diego, CA, USA) [75]. The results indicated that the ester-linked GnRH-Dox conjugates, including Zoptarelin Doxorubicin, showed significant toxicity at 100 nM and 1 uM, which was remarkably pronounced on the HCM cells. The cytotoxic effect was comparable to that of the free drug, especially at the highest concentration. In contrast, the conjugates with oxime-linked Dau showed no or only a minor toxicity on both the cell lines (Table 2). These data confirm that the linkage between the payload and homing peptide has a significant influence on early drug release and, consequently, an undesired toxic side effect. We may also conclude that the search for more suitable homing peptides might be more important than the application of cleavable bonds between the drug and the peptide to develop efficient DDSs."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00017	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	28.6 &plusmn; 5.5 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	72 h	.	.	"The main drug-related toxic side effect of anthracyclines is cardiotoxicity, leading to cardiomyopathy and heart failure. Comparative experiments to determine the cardiotoxicity of peptide-anthracycline conjugates with different linkages might be informative for the other conjugates with different types of drugs as well. For this purpose, human cardiomyocytes (HCM) and human umbilical vein endothelial cells (HUVEC) were used as models. The long-term (0-72 h) cytotoxic effect of sixteen GnRH-based conjugates containing Dox and Dau was determined by real-time impedimetric sensing using the xCELLigence SP system (ACEA Biosciences, San Diego, CA, USA) [75]. The results indicated that the ester-linked GnRH-Dox conjugates, including Zoptarelin Doxorubicin, showed significant toxicity at 100 nM and 1 uM, which was remarkably pronounced on the HCM cells. The cytotoxic effect was comparable to that of the free drug, especially at the highest concentration. In contrast, the conjugates with oxime-linked Dau showed no or only a minor toxicity on both the cell lines (Table 2). These data confirm that the linkage between the payload and homing peptide has a significant influence on early drug release and, consequently, an undesired toxic side effect. We may also conclude that the search for more suitable homing peptides might be more important than the application of cleavable bonds between the drug and the peptide to develop efficient DDSs."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00013	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	6.8 &plusmn; 1.0 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	72 h	.	.	"The main drug-related toxic side effect of anthracyclines is cardiotoxicity, leading to cardiomyopathy and heart failure. Comparative experiments to determine the cardiotoxicity of peptide-anthracycline conjugates with different linkages might be informative for the other conjugates with different types of drugs as well. For this purpose, human cardiomyocytes (HCM) and human umbilical vein endothelial cells (HUVEC) were used as models. The long-term (0-72 h) cytotoxic effect of sixteen GnRH-based conjugates containing Dox and Dau was determined by real-time impedimetric sensing using the xCELLigence SP system (ACEA Biosciences, San Diego, CA, USA) [75]. The results indicated that the ester-linked GnRH-Dox conjugates, including Zoptarelin Doxorubicin, showed significant toxicity at 100 nM and 1 uM, which was remarkably pronounced on the HCM cells. The cytotoxic effect was comparable to that of the free drug, especially at the highest concentration. In contrast, the conjugates with oxime-linked Dau showed no or only a minor toxicity on both the cell lines (Table 2). These data confirm that the linkage between the payload and homing peptide has a significant influence on early drug release and, consequently, an undesired toxic side effect. We may also conclude that the search for more suitable homing peptides might be more important than the application of cleavable bonds between the drug and the peptide to develop efficient DDSs."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00016	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	5.6 &plusmn; 2.0 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	72 h	.	.	"The main drug-related toxic side effect of anthracyclines is cardiotoxicity, leading to cardiomyopathy and heart failure. Comparative experiments to determine the cardiotoxicity of peptide-anthracycline conjugates with different linkages might be informative for the other conjugates with different types of drugs as well. For this purpose, human cardiomyocytes (HCM) and human umbilical vein endothelial cells (HUVEC) were used as models. The long-term (0-72 h) cytotoxic effect of sixteen GnRH-based conjugates containing Dox and Dau was determined by real-time impedimetric sensing using the xCELLigence SP system (ACEA Biosciences, San Diego, CA, USA) [75]. The results indicated that the ester-linked GnRH-Dox conjugates, including Zoptarelin Doxorubicin, showed significant toxicity at 100 nM and 1 uM, which was remarkably pronounced on the HCM cells. The cytotoxic effect was comparable to that of the free drug, especially at the highest concentration. In contrast, the conjugates with oxime-linked Dau showed no or only a minor toxicity on both the cell lines (Table 2). These data confirm that the linkage between the payload and homing peptide has a significant influence on early drug release and, consequently, an undesired toxic side effect. We may also conclude that the search for more suitable homing peptides might be more important than the application of cleavable bonds between the drug and the peptide to develop efficient DDSs."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00208	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	14.2 &plusmn; 3.2 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	72 h	.	.	"In our experiments, GnRH-III was applied as a targeting peptide. The conjugate [8Lys(Dau=Aoa-GFLG)]-GnRH-III, in which Dau was connected to the side chain of Lys in position 8 through an aminooxyacetylated cathepsin B-labile GFLG spacer, showed significant tumor growth inhibition in s.c.-developed fast-growing C26 murine colon cancer-bearing Balb/c mice. The effect highly depended on the treatment schedule. In the first attempt, the conjugate was administered i.p. at a dose of 8.86 umol (5 mg Dau-content/kg body weight) five times on days 7, 9, 11, 14 and 16 after tumor transplantation (Treatment schedule A). The tumor volume inhibition was only 15.7% on day 26 when the experiment finished. A slight enhancement in inhibition (22.3%) was detected when a dose of conjugate corresponding to 15 mg Dau content/kg body weight (26.6 &mu;mol) was injected only once on day 7 (Treatment schedule B). An additional treatment on day 10 (Treatment schedule C) did not result in any further improvements (21.9% on day 29). However, when the treatment schedule was changed to two treatments with the same dose on days 4 and 7, 46.3% inhibition was observed on day 29 (Treatment schedule D). In contrast, the treatments with free Dau at a dose of 2 mg/kg body weight (3.55 umol) on days 7, 9, 11, 14 and 16 showed only 22.6% inhibition on day 26. The median survival rates of the treated animals in comparison to the control group were 1 (A), 1.23 (B), 1.21 (C) and 1.38 (D), respectively, and 0.81 for free Dau. These results indicate the lower toxicity and the higher tumor volume inhibition effect of the conjugates in comparison with those of free Dau, as well as the importance of the treatment schedule. In another experiment, HT-29 human colon cancer was developed s.c. in immunodeficient SCID mice. Dau and two conjugates (with or without a GFLG spacer between the GnRH-III homing peptide and the payload) were used for the treatment. The first i.p. administrations were performed on day 13 after tumor inoculation. All the mice treated once with 2.5 mg/kg body weight (4.43 umol) free Dau died within 10 days. In contrast, the conjugates at a dose of 15 mg Dau content/kg body weight (26.6 umol) that refers to 52 mg/kg [8Lys(Dau=Aoa)]-GnRH-III and 62.5 mg/kg [8Lys(Dau=Aoa-GFLG)]-GnRH-III conjugates, respectively, did not show significant toxicity. The treatment was repeated on days 23 and 30. Because of the significant weight loss in several mice in the control group, the experiment was terminated on day 35. The tumor growth inhibition could be calculated as reductions in the tumor volume by 44.3% and 57.6% and the tumor weight by 41% and 50%, respectively. Interestingly, the conjugates were poorly effective on orthotopically developed tumors. In the case of the C26 colon tumor-bearing female Balb/c mice, only a 7% reduction in tumor weight was detected on day 13 after the two treatments on days 4 and 7 with [8Lys(Dau=Aoa)]-GnRH-III, at a 26.6 umol/kg (15 mg Dau content) dose. The effect of free Dau (2 mg/kg on days 4 and 7) showed a better inhibitory effect (24.4%). Interestingly, our novel developed GnRH-III derivative, in which Ser in position 4 was replaced by Lys(Ac), was much more potent, with 49.3% inhibition. It is worth mentioning that the rate of cellular uptake of the [4Lys(Ac), 8Lys(Dau=Aoa)]-GnRH-III conjugate by the tumor cells was significantly higher than that of the conjugate with the native GnRH-III sequence."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00015	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	19.4 &plusmn; 3.1 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	72 h	.	.	"In our experiments, GnRH-III was applied as a targeting peptide. The conjugate [8Lys(Dau=Aoa-GFLG)]-GnRH-III, in which Dau was connected to the side chain of Lys in position 8 through an aminooxyacetylated cathepsin B-labile GFLG spacer, showed significant tumor growth inhibition in s.c.-developed fast-growing C26 murine colon cancer-bearing Balb/c mice. The effect highly depended on the treatment schedule. In the first attempt, the conjugate was administered i.p. at a dose of 8.86 umol (5 mg Dau-content/kg body weight) five times on days 7, 9, 11, 14 and 16 after tumor transplantation (Treatment schedule A). The tumor volume inhibition was only 15.7% on day 26 when the experiment finished. A slight enhancement in inhibition (22.3%) was detected when a dose of conjugate corresponding to 15 mg Dau content/kg body weight (26.6 &mu;mol) was injected only once on day 7 (Treatment schedule B). An additional treatment on day 10 (Treatment schedule C) did not result in any further improvements (21.9% on day 29). However, when the treatment schedule was changed to two treatments with the same dose on days 4 and 7, 46.3% inhibition was observed on day 29 (Treatment schedule D). In contrast, the treatments with free Dau at a dose of 2 mg/kg body weight (3.55 umol) on days 7, 9, 11, 14 and 16 showed only 22.6% inhibition on day 26. The median survival rates of the treated animals in comparison to the control group were 1 (A), 1.23 (B), 1.21 (C) and 1.38 (D), respectively, and 0.81 for free Dau. These results indicate the lower toxicity and the higher tumor volume inhibition effect of the conjugates in comparison with those of free Dau, as well as the importance of the treatment schedule. In another experiment, HT-29 human colon cancer was developed s.c. in immunodeficient SCID mice. Dau and two conjugates (with or without a GFLG spacer between the GnRH-III homing peptide and the payload) were used for the treatment. The first i.p. administrations were performed on day 13 after tumor inoculation. All the mice treated once with 2.5 mg/kg body weight (4.43 umol) free Dau died within 10 days. In contrast, the conjugates at a dose of 15 mg Dau content/kg body weight (26.6 umol) that refers to 52 mg/kg [8Lys(Dau=Aoa)]-GnRH-III and 62.5 mg/kg [8Lys(Dau=Aoa-GFLG)]-GnRH-III conjugates, respectively, did not show significant toxicity. The treatment was repeated on days 23 and 30. Because of the significant weight loss in several mice in the control group, the experiment was terminated on day 35. The tumor growth inhibition could be calculated as reductions in the tumor volume by 44.3% and 57.6% and the tumor weight by 41% and 50%, respectively. Interestingly, the conjugates were poorly effective on orthotopically developed tumors. In the case of the C26 colon tumor-bearing female Balb/c mice, only a 7% reduction in tumor weight was detected on day 13 after the two treatments on days 4 and 7 with [8Lys(Dau=Aoa)]-GnRH-III, at a 26.6 umol/kg (15 mg Dau content) dose. The effect of free Dau (2 mg/kg on days 4 and 7) showed a better inhibitory effect (24.4%). Interestingly, our novel developed GnRH-III derivative, in which Ser in position 4 was replaced by Lys(Ac), was much more potent, with 49.3% inhibition. It is worth mentioning that the rate of cellular uptake of the [4Lys(Ac), 8Lys(Dau=Aoa)]-GnRH-III conjugate by the tumor cells was significantly higher than that of the conjugate with the native GnRH-III sequence."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00011	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	7.4 &plusmn; 2.6 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	72 h	.	.	"In our experiments, GnRH-III was applied as a targeting peptide. The conjugate [8Lys(Dau=Aoa-GFLG)]-GnRH-III, in which Dau was connected to the side chain of Lys in position 8 through an aminooxyacetylated cathepsin B-labile GFLG spacer, showed significant tumor growth inhibition in s.c.-developed fast-growing C26 murine colon cancer-bearing Balb/c mice. The effect highly depended on the treatment schedule. In the first attempt, the conjugate was administered i.p. at a dose of 8.86 umol (5 mg Dau-content/kg body weight) five times on days 7, 9, 11, 14 and 16 after tumor transplantation (Treatment schedule A). The tumor volume inhibition was only 15.7% on day 26 when the experiment finished. A slight enhancement in inhibition (22.3%) was detected when a dose of conjugate corresponding to 15 mg Dau content/kg body weight (26.6 &mu;mol) was injected only once on day 7 (Treatment schedule B). An additional treatment on day 10 (Treatment schedule C) did not result in any further improvements (21.9% on day 29). However, when the treatment schedule was changed to two treatments with the same dose on days 4 and 7, 46.3% inhibition was observed on day 29 (Treatment schedule D). In contrast, the treatments with free Dau at a dose of 2 mg/kg body weight (3.55 umol) on days 7, 9, 11, 14 and 16 showed only 22.6% inhibition on day 26. The median survival rates of the treated animals in comparison to the control group were 1 (A), 1.23 (B), 1.21 (C) and 1.38 (D), respectively, and 0.81 for free Dau. These results indicate the lower toxicity and the higher tumor volume inhibition effect of the conjugates in comparison with those of free Dau, as well as the importance of the treatment schedule. In another experiment, HT-29 human colon cancer was developed s.c. in immunodeficient SCID mice. Dau and two conjugates (with or without a GFLG spacer between the GnRH-III homing peptide and the payload) were used for the treatment. The first i.p. administrations were performed on day 13 after tumor inoculation. All the mice treated once with 2.5 mg/kg body weight (4.43 umol) free Dau died within 10 days. In contrast, the conjugates at a dose of 15 mg Dau content/kg body weight (26.6 umol) that refers to 52 mg/kg [8Lys(Dau=Aoa)]-GnRH-III and 62.5 mg/kg [8Lys(Dau=Aoa-GFLG)]-GnRH-III conjugates, respectively, did not show significant toxicity. The treatment was repeated on days 23 and 30. Because of the significant weight loss in several mice in the control group, the experiment was terminated on day 35. The tumor growth inhibition could be calculated as reductions in the tumor volume by 44.3% and 57.6% and the tumor weight by 41% and 50%, respectively. Interestingly, the conjugates were poorly effective on orthotopically developed tumors. In the case of the C26 colon tumor-bearing female Balb/c mice, only a 7% reduction in tumor weight was detected on day 13 after the two treatments on days 4 and 7 with [8Lys(Dau=Aoa)]-GnRH-III, at a 26.6 umol/kg (15 mg Dau content) dose. The effect of free Dau (2 mg/kg on days 4 and 7) showed a better inhibitory effect (24.4%). Interestingly, our novel developed GnRH-III derivative, in which Ser in position 4 was replaced by Lys(Ac), was much more potent, with 49.3% inhibition. It is worth mentioning that the rate of cellular uptake of the [4Lys(Ac), 8Lys(Dau=Aoa)]-GnRH-III conjugate by the tumor cells was significantly higher than that of the conjugate with the native GnRH-III sequence."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00205	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	2.2 &plusmn; 0.6 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	72 h	.	.	"In our experiments, GnRH-III was applied as a targeting peptide. The conjugate [8Lys(Dau=Aoa-GFLG)]-GnRH-III, in which Dau was connected to the side chain of Lys in position 8 through an aminooxyacetylated cathepsin B-labile GFLG spacer, showed significant tumor growth inhibition in s.c.-developed fast-growing C26 murine colon cancer-bearing Balb/c mice. The effect highly depended on the treatment schedule. In the first attempt, the conjugate was administered i.p. at a dose of 8.86 umol (5 mg Dau-content/kg body weight) five times on days 7, 9, 11, 14 and 16 after tumor transplantation (Treatment schedule A). The tumor volume inhibition was only 15.7% on day 26 when the experiment finished. A slight enhancement in inhibition (22.3%) was detected when a dose of conjugate corresponding to 15 mg Dau content/kg body weight (26.6 &mu;mol) was injected only once on day 7 (Treatment schedule B). An additional treatment on day 10 (Treatment schedule C) did not result in any further improvements (21.9% on day 29). However, when the treatment schedule was changed to two treatments with the same dose on days 4 and 7, 46.3% inhibition was observed on day 29 (Treatment schedule D). In contrast, the treatments with free Dau at a dose of 2 mg/kg body weight (3.55 umol) on days 7, 9, 11, 14 and 16 showed only 22.6% inhibition on day 26. The median survival rates of the treated animals in comparison to the control group were 1 (A), 1.23 (B), 1.21 (C) and 1.38 (D), respectively, and 0.81 for free Dau. These results indicate the lower toxicity and the higher tumor volume inhibition effect of the conjugates in comparison with those of free Dau, as well as the importance of the treatment schedule. In another experiment, HT-29 human colon cancer was developed s.c. in immunodeficient SCID mice. Dau and two conjugates (with or without a GFLG spacer between the GnRH-III homing peptide and the payload) were used for the treatment. The first i.p. administrations were performed on day 13 after tumor inoculation. All the mice treated once with 2.5 mg/kg body weight (4.43 umol) free Dau died within 10 days. In contrast, the conjugates at a dose of 15 mg Dau content/kg body weight (26.6 umol) that refers to 52 mg/kg [8Lys(Dau=Aoa)]-GnRH-III and 62.5 mg/kg [8Lys(Dau=Aoa-GFLG)]-GnRH-III conjugates, respectively, did not show significant toxicity. The treatment was repeated on days 23 and 30. Because of the significant weight loss in several mice in the control group, the experiment was terminated on day 35. The tumor growth inhibition could be calculated as reductions in the tumor volume by 44.3% and 57.6% and the tumor weight by 41% and 50%, respectively. Interestingly, the conjugates were poorly effective on orthotopically developed tumors. In the case of the C26 colon tumor-bearing female Balb/c mice, only a 7% reduction in tumor weight was detected on day 13 after the two treatments on days 4 and 7 with [8Lys(Dau=Aoa)]-GnRH-III, at a 26.6 umol/kg (15 mg Dau content) dose. The effect of free Dau (2 mg/kg on days 4 and 7) showed a better inhibitory effect (24.4%). Interestingly, our novel developed GnRH-III derivative, in which Ser in position 4 was replaced by Lys(Ac), was much more potent, with 49.3% inhibition. It is worth mentioning that the rate of cellular uptake of the [4Lys(Ac), 8Lys(Dau=Aoa)]-GnRH-III conjugate by the tumor cells was significantly higher than that of the conjugate with the native GnRH-III sequence."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00180	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	3.3 &plusmn; 0.9 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	72 h	.	.	"In our experiments, GnRH-III was applied as a targeting peptide. The conjugate [8Lys(Dau=Aoa-GFLG)]-GnRH-III, in which Dau was connected to the side chain of Lys in position 8 through an aminooxyacetylated cathepsin B-labile GFLG spacer, showed significant tumor growth inhibition in s.c.-developed fast-growing C26 murine colon cancer-bearing Balb/c mice. The effect highly depended on the treatment schedule. In the first attempt, the conjugate was administered i.p. at a dose of 8.86 umol (5 mg Dau-content/kg body weight) five times on days 7, 9, 11, 14 and 16 after tumor transplantation (Treatment schedule A). The tumor volume inhibition was only 15.7% on day 26 when the experiment finished. A slight enhancement in inhibition (22.3%) was detected when a dose of conjugate corresponding to 15 mg Dau content/kg body weight (26.6 &mu;mol) was injected only once on day 7 (Treatment schedule B). An additional treatment on day 10 (Treatment schedule C) did not result in any further improvements (21.9% on day 29). However, when the treatment schedule was changed to two treatments with the same dose on days 4 and 7, 46.3% inhibition was observed on day 29 (Treatment schedule D). In contrast, the treatments with free Dau at a dose of 2 mg/kg body weight (3.55 umol) on days 7, 9, 11, 14 and 16 showed only 22.6% inhibition on day 26. The median survival rates of the treated animals in comparison to the control group were 1 (A), 1.23 (B), 1.21 (C) and 1.38 (D), respectively, and 0.81 for free Dau. These results indicate the lower toxicity and the higher tumor volume inhibition effect of the conjugates in comparison with those of free Dau, as well as the importance of the treatment schedule. In another experiment, HT-29 human colon cancer was developed s.c. in immunodeficient SCID mice. Dau and two conjugates (with or without a GFLG spacer between the GnRH-III homing peptide and the payload) were used for the treatment. The first i.p. administrations were performed on day 13 after tumor inoculation. All the mice treated once with 2.5 mg/kg body weight (4.43 umol) free Dau died within 10 days. In contrast, the conjugates at a dose of 15 mg Dau content/kg body weight (26.6 umol) that refers to 52 mg/kg [8Lys(Dau=Aoa)]-GnRH-III and 62.5 mg/kg [8Lys(Dau=Aoa-GFLG)]-GnRH-III conjugates, respectively, did not show significant toxicity. The treatment was repeated on days 23 and 30. Because of the significant weight loss in several mice in the control group, the experiment was terminated on day 35. The tumor growth inhibition could be calculated as reductions in the tumor volume by 44.3% and 57.6% and the tumor weight by 41% and 50%, respectively. Interestingly, the conjugates were poorly effective on orthotopically developed tumors. In the case of the C26 colon tumor-bearing female Balb/c mice, only a 7% reduction in tumor weight was detected on day 13 after the two treatments on days 4 and 7 with [8Lys(Dau=Aoa)]-GnRH-III, at a 26.6 umol/kg (15 mg Dau content) dose. The effect of free Dau (2 mg/kg on days 4 and 7) showed a better inhibitory effect (24.4%). Interestingly, our novel developed GnRH-III derivative, in which Ser in position 4 was replaced by Lys(Ac), was much more potent, with 49.3% inhibition. It is worth mentioning that the rate of cellular uptake of the [4Lys(Ac), 8Lys(Dau=Aoa)]-GnRH-III conjugate by the tumor cells was significantly higher than that of the conjugate with the native GnRH-III sequence."	"The efficacy of current chemotherapeutic treatments against most solid tumors is limited by their systemic toxicity, which is partly associated with the cytotoxic properties of agents such as docetaxel or doxorubicin. To avoid or minimize adverse effects from chemotherapeutic molecules, a promising targeted approach is through peptide-drug conjugates (PDCs) that link anticancer molecules to peptides designed to interact with receptors highly expressed on cancer cells, and which can mediate the molecules rapid internalization within those cells. One such receptor is sortilin (SORT1), also known as neurotensin receptor3, a membranebound receptor that belongs to the VPS10P family of receptors. TH19P01 peptide was recently designed to target and exploit SORT1s ligand internalization function. Studies have confirmed that both TH1902 (a docetaxel-TH19P01 conjugate) and TH1904 (a doxorubicin-TH19P01 conjugate) require a SORT1-dependent mechanism of action to exert anticancer activities. In recent preclinical studies performed in immunocompromised animal models, which are unable to produce mature T-cells, TH1902 was effective against several human SORT1-positive xenograft models including triple-negative breast cancer (TNBC), ovarian cancer, and endometrial cancer."
REF00296	PDC_00109	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.38 &plusmn; 0.33 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"Like GnRH and somatostatin, bombesin (BBN) is another example of peptide hor-556 mone which receptors are overexpressed in cancerous tissues. This 14-mer peptide (Glp-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2), first discovered in the skin of the frog Bombina bombina, is associated with the gastrin-releasing peptide (GRP) as a mammalian counterpart. The bombesin receptor family comprises neuromedin receptor B (NMB-R, or BB1), gastrin-releasing peptide receptor (GRP-R, or BB2) and bombesin receptor subtype 3 (BRS-3, or BB3). Among them, GRP-R has been the most investigated so far and has been proven to be upregulated in breast, prostate, pancreas, small-cell lung cancers, among others, hence representing a suitable target for drug delivery to tumors. Many attempts have been made to modify and shorten the sequence of bombesin to tailor its stability, activity (agonist or antagonist), affinity and selectivity towards this receptor. Several research groups have encouraged the use of their optimized structures as putative drug delivery systems, but they were never directly compared. Moreover, the previous examples of conjugates between GRP-R ligands and anthracyclines display a labile ester bond that could cause the early release of the drug in vivo. Therefore, our group took the leap and produced conjugates based on the most promising bombesin analogs as homing devices attached to Dau via an oxime bond and two cathepsin B-cleavable linkers (LRRY or GFLG). Furthermore, a conjugate bearing a novel developed bombesin analog ([6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14)) was synthesized. The use of oxime-linked Dau as a payload promoted the identification of three conjugates with improved cytostatic activity and cellular uptake by human prostate (PC-3) and breast cancer (MDA-MB-231 and MDA-MB-453) cell lines. The Dau=Aoa-Leu-OH active metabolite was readily released in all the cases in less than 30 min in rat liver lysosomal homogenate, but only L5 (Dau=Aoa-LRRY-[6D-Phe, 13Sta, 14Leu]-BBN(7-14), where Sta is statine) and L6 Dau=Aoa-LRRY-[6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14) demonstrated a satisfactory stability in the mouse plasma. Therefore, only these two conjugates were further investigated in vivo. As mentioned above, their chronic toxicity was assessed in healthy mice by administering the conjugates doses of 5, 10 and 20 mg Dau content/kg body weight. The PDCs were not critically harmful at any dose, although a relatively high mouse weight loss (10-15%) was induced at the highest dose. The in vivo antitumor efficacy was studied in murine xenograft models bearing s.c.-inoculated PC-3 human prostatic adenocarcinoma. The conjugates were administered intraperitoneally every fifth day starting from day 9 after tumor inoculation, for a total of five treatments, at a dose of 10 mg Dau-content/kg body weight, and their tumor growth inhibition values were compared to those of the mice treated with the maximum tolerated dose of free Dau (1 mg/kg) and 0.9% saline solution (control group). On the last day of the experiment (day 33), L5 and L6 revealed reductions in the tumor size by 21.4% and 31.4% and tumor weights by 16.6% and 33.1% compared to those of the control, respectively. On the other hand, the Dau-treated group had to be terminated on day 26 because of severe toxicity, without showing a significant reduction in the tumor volume and weight. To better understand the long-term effect of the newly developed compounds, the tumor doubling time (DT) was calculated; both the PDCs significantly increased the DT compared to the treatment with free Dau."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00108	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.22 &plusmn; 0.19 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"Like GnRH and somatostatin, bombesin (BBN) is another example of peptide hor-556 mone which receptors are overexpressed in cancerous tissues. This 14-mer peptide (Glp-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2), first discovered in the skin of the frog Bombina bombina, is associated with the gastrin-releasing peptide (GRP) as a mammalian counterpart. The bombesin receptor family comprises neuromedin receptor B (NMB-R, or BB1), gastrin-releasing peptide receptor (GRP-R, or BB2) and bombesin receptor subtype 3 (BRS-3, or BB3). Among them, GRP-R has been the most investigated so far and has been proven to be upregulated in breast, prostate, pancreas, small-cell lung cancers, among others, hence representing a suitable target for drug delivery to tumors. Many attempts have been made to modify and shorten the sequence of bombesin to tailor its stability, activity (agonist or antagonist), affinity and selectivity towards this receptor. Several research groups have encouraged the use of their optimized structures as putative drug delivery systems, but they were never directly compared. Moreover, the previous examples of conjugates between GRP-R ligands and anthracyclines display a labile ester bond that could cause the early release of the drug in vivo. Therefore, our group took the leap and produced conjugates based on the most promising bombesin analogs as homing devices attached to Dau via an oxime bond and two cathepsin B-cleavable linkers (LRRY or GFLG). Furthermore, a conjugate bearing a novel developed bombesin analog ([6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14)) was synthesized. The use of oxime-linked Dau as a payload promoted the identification of three conjugates with improved cytostatic activity and cellular uptake by human prostate (PC-3) and breast cancer (MDA-MB-231 and MDA-MB-453) cell lines. The Dau=Aoa-Leu-OH active metabolite was readily released in all the cases in less than 30 min in rat liver lysosomal homogenate, but only L5 (Dau=Aoa-LRRY-[6D-Phe, 13Sta, 14Leu]-BBN(7-14), where Sta is statine) and L6 Dau=Aoa-LRRY-[6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14) demonstrated a satisfactory stability in the mouse plasma. Therefore, only these two conjugates were further investigated in vivo. As mentioned above, their chronic toxicity was assessed in healthy mice by administering the conjugates doses of 5, 10 and 20 mg Dau content/kg body weight. The PDCs were not critically harmful at any dose, although a relatively high mouse weight loss (10-15%) was induced at the highest dose. The in vivo antitumor efficacy was studied in murine xenograft models bearing s.c.-inoculated PC-3 human prostatic adenocarcinoma. The conjugates were administered intraperitoneally every fifth day starting from day 9 after tumor inoculation, for a total of five treatments, at a dose of 10 mg Dau-content/kg body weight, and their tumor growth inhibition values were compared to those of the mice treated with the maximum tolerated dose of free Dau (1 mg/kg) and 0.9% saline solution (control group). On the last day of the experiment (day 33), L5 and L6 revealed reductions in the tumor size by 21.4% and 31.4% and tumor weights by 16.6% and 33.1% compared to those of the control, respectively. On the other hand, the Dau-treated group had to be terminated on day 26 because of severe toxicity, without showing a significant reduction in the tumor volume and weight. To better understand the long-term effect of the newly developed compounds, the tumor doubling time (DT) was calculated; both the PDCs significantly increased the DT compared to the treatment with free Dau."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00107	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	18.04 &plusmn; 3.01 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"Like GnRH and somatostatin, bombesin (BBN) is another example of peptide hor-556 mone which receptors are overexpressed in cancerous tissues. This 14-mer peptide (Glp-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2), first discovered in the skin of the frog Bombina bombina, is associated with the gastrin-releasing peptide (GRP) as a mammalian counterpart. The bombesin receptor family comprises neuromedin receptor B (NMB-R, or BB1), gastrin-releasing peptide receptor (GRP-R, or BB2) and bombesin receptor subtype 3 (BRS-3, or BB3). Among them, GRP-R has been the most investigated so far and has been proven to be upregulated in breast, prostate, pancreas, small-cell lung cancers, among others, hence representing a suitable target for drug delivery to tumors. Many attempts have been made to modify and shorten the sequence of bombesin to tailor its stability, activity (agonist or antagonist), affinity and selectivity towards this receptor. Several research groups have encouraged the use of their optimized structures as putative drug delivery systems, but they were never directly compared. Moreover, the previous examples of conjugates between GRP-R ligands and anthracyclines display a labile ester bond that could cause the early release of the drug in vivo. Therefore, our group took the leap and produced conjugates based on the most promising bombesin analogs as homing devices attached to Dau via an oxime bond and two cathepsin B-cleavable linkers (LRRY or GFLG). Furthermore, a conjugate bearing a novel developed bombesin analog ([6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14)) was synthesized. The use of oxime-linked Dau as a payload promoted the identification of three conjugates with improved cytostatic activity and cellular uptake by human prostate (PC-3) and breast cancer (MDA-MB-231 and MDA-MB-453) cell lines. The Dau=Aoa-Leu-OH active metabolite was readily released in all the cases in less than 30 min in rat liver lysosomal homogenate, but only L5 (Dau=Aoa-LRRY-[6D-Phe, 13Sta, 14Leu]-BBN(7-14), where Sta is statine) and L6 Dau=Aoa-LRRY-[6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14) demonstrated a satisfactory stability in the mouse plasma. Therefore, only these two conjugates were further investigated in vivo. As mentioned above, their chronic toxicity was assessed in healthy mice by administering the conjugates doses of 5, 10 and 20 mg Dau content/kg body weight. The PDCs were not critically harmful at any dose, although a relatively high mouse weight loss (10-15%) was induced at the highest dose. The in vivo antitumor efficacy was studied in murine xenograft models bearing s.c.-inoculated PC-3 human prostatic adenocarcinoma. The conjugates were administered intraperitoneally every fifth day starting from day 9 after tumor inoculation, for a total of five treatments, at a dose of 10 mg Dau-content/kg body weight, and their tumor growth inhibition values were compared to those of the mice treated with the maximum tolerated dose of free Dau (1 mg/kg) and 0.9% saline solution (control group). On the last day of the experiment (day 33), L5 and L6 revealed reductions in the tumor size by 21.4% and 31.4% and tumor weights by 16.6% and 33.1% compared to those of the control, respectively. On the other hand, the Dau-treated group had to be terminated on day 26 because of severe toxicity, without showing a significant reduction in the tumor volume and weight. To better understand the long-term effect of the newly developed compounds, the tumor doubling time (DT) was calculated; both the PDCs significantly increased the DT compared to the treatment with free Dau."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00109	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	22.92 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"Like GnRH and somatostatin, bombesin (BBN) is another example of peptide hor-556 mone which receptors are overexpressed in cancerous tissues. This 14-mer peptide (Glp-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2), first discovered in the skin of the frog Bombina bombina, is associated with the gastrin-releasing peptide (GRP) as a mammalian counterpart. The bombesin receptor family comprises neuromedin receptor B (NMB-R, or BB1), gastrin-releasing peptide receptor (GRP-R, or BB2) and bombesin receptor subtype 3 (BRS-3, or BB3). Among them, GRP-R has been the most investigated so far and has been proven to be upregulated in breast, prostate, pancreas, small-cell lung cancers, among others, hence representing a suitable target for drug delivery to tumors. Many attempts have been made to modify and shorten the sequence of bombesin to tailor its stability, activity (agonist or antagonist), affinity and selectivity towards this receptor. Several research groups have encouraged the use of their optimized structures as putative drug delivery systems, but they were never directly compared. Moreover, the previous examples of conjugates between GRP-R ligands and anthracyclines display a labile ester bond that could cause the early release of the drug in vivo. Therefore, our group took the leap and produced conjugates based on the most promising bombesin analogs as homing devices attached to Dau via an oxime bond and two cathepsin B-cleavable linkers (LRRY or GFLG). Furthermore, a conjugate bearing a novel developed bombesin analog ([6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14)) was synthesized. The use of oxime-linked Dau as a payload promoted the identification of three conjugates with improved cytostatic activity and cellular uptake by human prostate (PC-3) and breast cancer (MDA-MB-231 and MDA-MB-453) cell lines. The Dau=Aoa-Leu-OH active metabolite was readily released in all the cases in less than 30 min in rat liver lysosomal homogenate, but only L5 (Dau=Aoa-LRRY-[6D-Phe, 13Sta, 14Leu]-BBN(7-14), where Sta is statine) and L6 Dau=Aoa-LRRY-[6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14) demonstrated a satisfactory stability in the mouse plasma. Therefore, only these two conjugates were further investigated in vivo. As mentioned above, their chronic toxicity was assessed in healthy mice by administering the conjugates doses of 5, 10 and 20 mg Dau content/kg body weight. The PDCs were not critically harmful at any dose, although a relatively high mouse weight loss (10-15%) was induced at the highest dose. The in vivo antitumor efficacy was studied in murine xenograft models bearing s.c.-inoculated PC-3 human prostatic adenocarcinoma. The conjugates were administered intraperitoneally every fifth day starting from day 9 after tumor inoculation, for a total of five treatments, at a dose of 10 mg Dau-content/kg body weight, and their tumor growth inhibition values were compared to those of the mice treated with the maximum tolerated dose of free Dau (1 mg/kg) and 0.9% saline solution (control group). On the last day of the experiment (day 33), L5 and L6 revealed reductions in the tumor size by 21.4% and 31.4% and tumor weights by 16.6% and 33.1% compared to those of the control, respectively. On the other hand, the Dau-treated group had to be terminated on day 26 because of severe toxicity, without showing a significant reduction in the tumor volume and weight. To better understand the long-term effect of the newly developed compounds, the tumor doubling time (DT) was calculated; both the PDCs significantly increased the DT compared to the treatment with free Dau."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00108	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	12.35 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"Like GnRH and somatostatin, bombesin (BBN) is another example of peptide hor-556 mone which receptors are overexpressed in cancerous tissues. This 14-mer peptide (Glp-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2), first discovered in the skin of the frog Bombina bombina, is associated with the gastrin-releasing peptide (GRP) as a mammalian counterpart. The bombesin receptor family comprises neuromedin receptor B (NMB-R, or BB1), gastrin-releasing peptide receptor (GRP-R, or BB2) and bombesin receptor subtype 3 (BRS-3, or BB3). Among them, GRP-R has been the most investigated so far and has been proven to be upregulated in breast, prostate, pancreas, small-cell lung cancers, among others, hence representing a suitable target for drug delivery to tumors. Many attempts have been made to modify and shorten the sequence of bombesin to tailor its stability, activity (agonist or antagonist), affinity and selectivity towards this receptor. Several research groups have encouraged the use of their optimized structures as putative drug delivery systems, but they were never directly compared. Moreover, the previous examples of conjugates between GRP-R ligands and anthracyclines display a labile ester bond that could cause the early release of the drug in vivo. Therefore, our group took the leap and produced conjugates based on the most promising bombesin analogs as homing devices attached to Dau via an oxime bond and two cathepsin B-cleavable linkers (LRRY or GFLG). Furthermore, a conjugate bearing a novel developed bombesin analog ([6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14)) was synthesized. The use of oxime-linked Dau as a payload promoted the identification of three conjugates with improved cytostatic activity and cellular uptake by human prostate (PC-3) and breast cancer (MDA-MB-231 and MDA-MB-453) cell lines. The Dau=Aoa-Leu-OH active metabolite was readily released in all the cases in less than 30 min in rat liver lysosomal homogenate, but only L5 (Dau=Aoa-LRRY-[6D-Phe, 13Sta, 14Leu]-BBN(7-14), where Sta is statine) and L6 Dau=Aoa-LRRY-[6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14) demonstrated a satisfactory stability in the mouse plasma. Therefore, only these two conjugates were further investigated in vivo. As mentioned above, their chronic toxicity was assessed in healthy mice by administering the conjugates doses of 5, 10 and 20 mg Dau content/kg body weight. The PDCs were not critically harmful at any dose, although a relatively high mouse weight loss (10-15%) was induced at the highest dose. The in vivo antitumor efficacy was studied in murine xenograft models bearing s.c.-inoculated PC-3 human prostatic adenocarcinoma. The conjugates were administered intraperitoneally every fifth day starting from day 9 after tumor inoculation, for a total of five treatments, at a dose of 10 mg Dau-content/kg body weight, and their tumor growth inhibition values were compared to those of the mice treated with the maximum tolerated dose of free Dau (1 mg/kg) and 0.9% saline solution (control group). On the last day of the experiment (day 33), L5 and L6 revealed reductions in the tumor size by 21.4% and 31.4% and tumor weights by 16.6% and 33.1% compared to those of the control, respectively. On the other hand, the Dau-treated group had to be terminated on day 26 because of severe toxicity, without showing a significant reduction in the tumor volume and weight. To better understand the long-term effect of the newly developed compounds, the tumor doubling time (DT) was calculated; both the PDCs significantly increased the DT compared to the treatment with free Dau."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00107	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	16.09 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"Like GnRH and somatostatin, bombesin (BBN) is another example of peptide hor-556 mone which receptors are overexpressed in cancerous tissues. This 14-mer peptide (Glp-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2), first discovered in the skin of the frog Bombina bombina, is associated with the gastrin-releasing peptide (GRP) as a mammalian counterpart. The bombesin receptor family comprises neuromedin receptor B (NMB-R, or BB1), gastrin-releasing peptide receptor (GRP-R, or BB2) and bombesin receptor subtype 3 (BRS-3, or BB3). Among them, GRP-R has been the most investigated so far and has been proven to be upregulated in breast, prostate, pancreas, small-cell lung cancers, among others, hence representing a suitable target for drug delivery to tumors. Many attempts have been made to modify and shorten the sequence of bombesin to tailor its stability, activity (agonist or antagonist), affinity and selectivity towards this receptor. Several research groups have encouraged the use of their optimized structures as putative drug delivery systems, but they were never directly compared. Moreover, the previous examples of conjugates between GRP-R ligands and anthracyclines display a labile ester bond that could cause the early release of the drug in vivo. Therefore, our group took the leap and produced conjugates based on the most promising bombesin analogs as homing devices attached to Dau via an oxime bond and two cathepsin B-cleavable linkers (LRRY or GFLG). Furthermore, a conjugate bearing a novel developed bombesin analog ([6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14)) was synthesized. The use of oxime-linked Dau as a payload promoted the identification of three conjugates with improved cytostatic activity and cellular uptake by human prostate (PC-3) and breast cancer (MDA-MB-231 and MDA-MB-453) cell lines. The Dau=Aoa-Leu-OH active metabolite was readily released in all the cases in less than 30 min in rat liver lysosomal homogenate, but only L5 (Dau=Aoa-LRRY-[6D-Phe, 13Sta, 14Leu]-BBN(7-14), where Sta is statine) and L6 Dau=Aoa-LRRY-[6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14) demonstrated a satisfactory stability in the mouse plasma. Therefore, only these two conjugates were further investigated in vivo. As mentioned above, their chronic toxicity was assessed in healthy mice by administering the conjugates doses of 5, 10 and 20 mg Dau content/kg body weight. The PDCs were not critically harmful at any dose, although a relatively high mouse weight loss (10-15%) was induced at the highest dose. The in vivo antitumor efficacy was studied in murine xenograft models bearing s.c.-inoculated PC-3 human prostatic adenocarcinoma. The conjugates were administered intraperitoneally every fifth day starting from day 9 after tumor inoculation, for a total of five treatments, at a dose of 10 mg Dau-content/kg body weight, and their tumor growth inhibition values were compared to those of the mice treated with the maximum tolerated dose of free Dau (1 mg/kg) and 0.9% saline solution (control group). On the last day of the experiment (day 33), L5 and L6 revealed reductions in the tumor size by 21.4% and 31.4% and tumor weights by 16.6% and 33.1% compared to those of the control, respectively. On the other hand, the Dau-treated group had to be terminated on day 26 because of severe toxicity, without showing a significant reduction in the tumor volume and weight. To better understand the long-term effect of the newly developed compounds, the tumor doubling time (DT) was calculated; both the PDCs significantly increased the DT compared to the treatment with free Dau."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00108	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Drug concentration	21.40%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"Like GnRH and somatostatin, bombesin (BBN) is another example of peptide hor-556 mone which receptors are overexpressed in cancerous tissues. This 14-mer peptide (Glp-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2), first discovered in the skin of the frog Bombina bombina, is associated with the gastrin-releasing peptide (GRP) as a mammalian counterpart. The bombesin receptor family comprises neuromedin receptor B (NMB-R, or BB1), gastrin-releasing peptide receptor (GRP-R, or BB2) and bombesin receptor subtype 3 (BRS-3, or BB3). Among them, GRP-R has been the most investigated so far and has been proven to be upregulated in breast, prostate, pancreas, small-cell lung cancers, among others, hence representing a suitable target for drug delivery to tumors. Many attempts have been made to modify and shorten the sequence of bombesin to tailor its stability, activity (agonist or antagonist), affinity and selectivity towards this receptor. Several research groups have encouraged the use of their optimized structures as putative drug delivery systems, but they were never directly compared. Moreover, the previous examples of conjugates between GRP-R ligands and anthracyclines display a labile ester bond that could cause the early release of the drug in vivo. Therefore, our group took the leap and produced conjugates based on the most promising bombesin analogs as homing devices attached to Dau via an oxime bond and two cathepsin B-cleavable linkers (LRRY or GFLG). Furthermore, a conjugate bearing a novel developed bombesin analog ([6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14)) was synthesized. The use of oxime-linked Dau as a payload promoted the identification of three conjugates with improved cytostatic activity and cellular uptake by human prostate (PC-3) and breast cancer (MDA-MB-231 and MDA-MB-453) cell lines. The Dau=Aoa-Leu-OH active metabolite was readily released in all the cases in less than 30 min in rat liver lysosomal homogenate, but only L5 (Dau=Aoa-LRRY-[6D-Phe, 13Sta, 14Leu]-BBN(7-14), where Sta is statine) and L6 Dau=Aoa-LRRY-[6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14) demonstrated a satisfactory stability in the mouse plasma. Therefore, only these two conjugates were further investigated in vivo. As mentioned above, their chronic toxicity was assessed in healthy mice by administering the conjugates doses of 5, 10 and 20 mg Dau content/kg body weight. The PDCs were not critically harmful at any dose, although a relatively high mouse weight loss (10-15%) was induced at the highest dose. The in vivo antitumor efficacy was studied in murine xenograft models bearing s.c.-inoculated PC-3 human prostatic adenocarcinoma. The conjugates were administered intraperitoneally every fifth day starting from day 9 after tumor inoculation, for a total of five treatments, at a dose of 10 mg Dau-content/kg body weight, and their tumor growth inhibition values were compared to those of the mice treated with the maximum tolerated dose of free Dau (1 mg/kg) and 0.9% saline solution (control group). On the last day of the experiment (day 33), L5 and L6 revealed reductions in the tumor size by 21.4% and 31.4% and tumor weights by 16.6% and 33.1% compared to those of the control, respectively. On the other hand, the Dau-treated group had to be terminated on day 26 because of severe toxicity, without showing a significant reduction in the tumor volume and weight. To better understand the long-term effect of the newly developed compounds, the tumor doubling time (DT) was calculated; both the PDCs significantly increased the DT compared to the treatment with free Dau."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00107	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Drug concentration	31.40%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"Like GnRH and somatostatin, bombesin (BBN) is another example of peptide hor-556 mone which receptors are overexpressed in cancerous tissues. This 14-mer peptide (Glp-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2), first discovered in the skin of the frog Bombina bombina, is associated with the gastrin-releasing peptide (GRP) as a mammalian counterpart. The bombesin receptor family comprises neuromedin receptor B (NMB-R, or BB1), gastrin-releasing peptide receptor (GRP-R, or BB2) and bombesin receptor subtype 3 (BRS-3, or BB3). Among them, GRP-R has been the most investigated so far and has been proven to be upregulated in breast, prostate, pancreas, small-cell lung cancers, among others, hence representing a suitable target for drug delivery to tumors. Many attempts have been made to modify and shorten the sequence of bombesin to tailor its stability, activity (agonist or antagonist), affinity and selectivity towards this receptor. Several research groups have encouraged the use of their optimized structures as putative drug delivery systems, but they were never directly compared. Moreover, the previous examples of conjugates between GRP-R ligands and anthracyclines display a labile ester bond that could cause the early release of the drug in vivo. Therefore, our group took the leap and produced conjugates based on the most promising bombesin analogs as homing devices attached to Dau via an oxime bond and two cathepsin B-cleavable linkers (LRRY or GFLG). Furthermore, a conjugate bearing a novel developed bombesin analog ([6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14)) was synthesized. The use of oxime-linked Dau as a payload promoted the identification of three conjugates with improved cytostatic activity and cellular uptake by human prostate (PC-3) and breast cancer (MDA-MB-231 and MDA-MB-453) cell lines. The Dau=Aoa-Leu-OH active metabolite was readily released in all the cases in less than 30 min in rat liver lysosomal homogenate, but only L5 (Dau=Aoa-LRRY-[6D-Phe, 13Sta, 14Leu]-BBN(7-14), where Sta is statine) and L6 Dau=Aoa-LRRY-[6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14) demonstrated a satisfactory stability in the mouse plasma. Therefore, only these two conjugates were further investigated in vivo. As mentioned above, their chronic toxicity was assessed in healthy mice by administering the conjugates doses of 5, 10 and 20 mg Dau content/kg body weight. The PDCs were not critically harmful at any dose, although a relatively high mouse weight loss (10-15%) was induced at the highest dose. The in vivo antitumor efficacy was studied in murine xenograft models bearing s.c.-inoculated PC-3 human prostatic adenocarcinoma. The conjugates were administered intraperitoneally every fifth day starting from day 9 after tumor inoculation, for a total of five treatments, at a dose of 10 mg Dau-content/kg body weight, and their tumor growth inhibition values were compared to those of the mice treated with the maximum tolerated dose of free Dau (1 mg/kg) and 0.9% saline solution (control group). On the last day of the experiment (day 33), L5 and L6 revealed reductions in the tumor size by 21.4% and 31.4% and tumor weights by 16.6% and 33.1% compared to those of the control, respectively. On the other hand, the Dau-treated group had to be terminated on day 26 because of severe toxicity, without showing a significant reduction in the tumor volume and weight. To better understand the long-term effect of the newly developed compounds, the tumor doubling time (DT) was calculated; both the PDCs significantly increased the DT compared to the treatment with free Dau."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00108	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor weight inhibition	16.60%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"Like GnRH and somatostatin, bombesin (BBN) is another example of peptide hor-556 mone which receptors are overexpressed in cancerous tissues. This 14-mer peptide (Glp-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2), first discovered in the skin of the frog Bombina bombina, is associated with the gastrin-releasing peptide (GRP) as a mammalian counterpart. The bombesin receptor family comprises neuromedin receptor B (NMB-R, or BB1), gastrin-releasing peptide receptor (GRP-R, or BB2) and bombesin receptor subtype 3 (BRS-3, or BB3). Among them, GRP-R has been the most investigated so far and has been proven to be upregulated in breast, prostate, pancreas, small-cell lung cancers, among others, hence representing a suitable target for drug delivery to tumors. Many attempts have been made to modify and shorten the sequence of bombesin to tailor its stability, activity (agonist or antagonist), affinity and selectivity towards this receptor. Several research groups have encouraged the use of their optimized structures as putative drug delivery systems, but they were never directly compared. Moreover, the previous examples of conjugates between GRP-R ligands and anthracyclines display a labile ester bond that could cause the early release of the drug in vivo. Therefore, our group took the leap and produced conjugates based on the most promising bombesin analogs as homing devices attached to Dau via an oxime bond and two cathepsin B-cleavable linkers (LRRY or GFLG). Furthermore, a conjugate bearing a novel developed bombesin analog ([6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14)) was synthesized. The use of oxime-linked Dau as a payload promoted the identification of three conjugates with improved cytostatic activity and cellular uptake by human prostate (PC-3) and breast cancer (MDA-MB-231 and MDA-MB-453) cell lines. The Dau=Aoa-Leu-OH active metabolite was readily released in all the cases in less than 30 min in rat liver lysosomal homogenate, but only L5 (Dau=Aoa-LRRY-[6D-Phe, 13Sta, 14Leu]-BBN(7-14), where Sta is statine) and L6 Dau=Aoa-LRRY-[6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14) demonstrated a satisfactory stability in the mouse plasma. Therefore, only these two conjugates were further investigated in vivo. As mentioned above, their chronic toxicity was assessed in healthy mice by administering the conjugates doses of 5, 10 and 20 mg Dau content/kg body weight. The PDCs were not critically harmful at any dose, although a relatively high mouse weight loss (10-15%) was induced at the highest dose. The in vivo antitumor efficacy was studied in murine xenograft models bearing s.c.-inoculated PC-3 human prostatic adenocarcinoma. The conjugates were administered intraperitoneally every fifth day starting from day 9 after tumor inoculation, for a total of five treatments, at a dose of 10 mg Dau-content/kg body weight, and their tumor growth inhibition values were compared to those of the mice treated with the maximum tolerated dose of free Dau (1 mg/kg) and 0.9% saline solution (control group). On the last day of the experiment (day 33), L5 and L6 revealed reductions in the tumor size by 21.4% and 31.4% and tumor weights by 16.6% and 33.1% compared to those of the control, respectively. On the other hand, the Dau-treated group had to be terminated on day 26 because of severe toxicity, without showing a significant reduction in the tumor volume and weight. To better understand the long-term effect of the newly developed compounds, the tumor doubling time (DT) was calculated; both the PDCs significantly increased the DT compared to the treatment with free Dau."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00296	PDC_00107	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor weight inhibition	33.10%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"Like GnRH and somatostatin, bombesin (BBN) is another example of peptide hor-556 mone which receptors are overexpressed in cancerous tissues. This 14-mer peptide (Glp-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2), first discovered in the skin of the frog Bombina bombina, is associated with the gastrin-releasing peptide (GRP) as a mammalian counterpart. The bombesin receptor family comprises neuromedin receptor B (NMB-R, or BB1), gastrin-releasing peptide receptor (GRP-R, or BB2) and bombesin receptor subtype 3 (BRS-3, or BB3). Among them, GRP-R has been the most investigated so far and has been proven to be upregulated in breast, prostate, pancreas, small-cell lung cancers, among others, hence representing a suitable target for drug delivery to tumors. Many attempts have been made to modify and shorten the sequence of bombesin to tailor its stability, activity (agonist or antagonist), affinity and selectivity towards this receptor. Several research groups have encouraged the use of their optimized structures as putative drug delivery systems, but they were never directly compared. Moreover, the previous examples of conjugates between GRP-R ligands and anthracyclines display a labile ester bond that could cause the early release of the drug in vivo. Therefore, our group took the leap and produced conjugates based on the most promising bombesin analogs as homing devices attached to Dau via an oxime bond and two cathepsin B-cleavable linkers (LRRY or GFLG). Furthermore, a conjugate bearing a novel developed bombesin analog ([6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14)) was synthesized. The use of oxime-linked Dau as a payload promoted the identification of three conjugates with improved cytostatic activity and cellular uptake by human prostate (PC-3) and breast cancer (MDA-MB-231 and MDA-MB-453) cell lines. The Dau=Aoa-Leu-OH active metabolite was readily released in all the cases in less than 30 min in rat liver lysosomal homogenate, but only L5 (Dau=Aoa-LRRY-[6D-Phe, 13Sta, 14Leu]-BBN(7-14), where Sta is statine) and L6 Dau=Aoa-LRRY-[6D-Phe, 11-Ala, 13Sta, 14Nle]-BBN(7-14) demonstrated a satisfactory stability in the mouse plasma. Therefore, only these two conjugates were further investigated in vivo. As mentioned above, their chronic toxicity was assessed in healthy mice by administering the conjugates doses of 5, 10 and 20 mg Dau content/kg body weight. The PDCs were not critically harmful at any dose, although a relatively high mouse weight loss (10-15%) was induced at the highest dose. The in vivo antitumor efficacy was studied in murine xenograft models bearing s.c.-inoculated PC-3 human prostatic adenocarcinoma. The conjugates were administered intraperitoneally every fifth day starting from day 9 after tumor inoculation, for a total of five treatments, at a dose of 10 mg Dau-content/kg body weight, and their tumor growth inhibition values were compared to those of the mice treated with the maximum tolerated dose of free Dau (1 mg/kg) and 0.9% saline solution (control group). On the last day of the experiment (day 33), L5 and L6 revealed reductions in the tumor size by 21.4% and 31.4% and tumor weights by 16.6% and 33.1% compared to those of the control, respectively. On the other hand, the Dau-treated group had to be terminated on day 26 because of severe toxicity, without showing a significant reduction in the tumor volume and weight. To better understand the long-term effect of the newly developed compounds, the tumor doubling time (DT) was calculated; both the PDCs significantly increased the DT compared to the treatment with free Dau."	"The crucial steps during the synthesis of aminooxyacetylated peptides are the incorporation of aminooxyacetic acid (Aoa), including a protecting group, and the final cleavage and the working-up procedure of the Aoa-containing peptide derivatives. In most cases, Boc-protected Aoa is attached to a peptide chain in the last step of solid-phase peptide synthesis. It has been observed that over-acylation (additional Boc-Aoa-OH connected to the Aoa moiety) may occur as the main side reaction. Many approaches have been investigated to overcome this problem, including carbodiimide-mediated one-pot acylation without a base or the application of Boc-Aoa-OSu active ester as an acylating agent, as well as the use of a high excess (8 equiv) of Boc-Aoa-OH and coupling agents for a short acylation time (10 min). Nevertheless, the coupling of the diBoc-protected Aoa derivative has proved to be the best solution. However, the aminooxyacetyl moiety is very sensitive to molecules containing carbonyl groups, with the partial impact of the peptide sequence. Therefore, the free NH2-O-R group reacts often with these compounds during the working-up procedure after the final cleavage of Aoa-modified peptides from the resin. These carbonyl group-containing derivatives might come from the plastic tubes or residues of acetone used in a laboratory. This cannot be prevented even by using diBoc-protected Aoa or working in argon. We found a highly sensitive peptide to this side reaction; the synthesis of a somatostatin analog developed in Schallys laboratory elongated with Aoa (H-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) was unsuccessful. After several trials to optimize the reaction conditions, we elaborated the following procedure: The semi-protected peptide H-D-Phe-Cys-Tyr-D-Trp-Lys(Dde)-Val-Cys-Thr-NH2 was cleaved from Rink Amide MBHA resin and reacted with Boc-Aoa-OPcp to incorporate Aoa into the N-terminus in a solution. After the efficient coupling reaction, the Dde-protecting group was removed with 2% hydrazine in DMF. Surprisingly, during the cleavage of Dde, a cyclic peptide also formed (Boc-Aoa-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2). The Boc group was cleaved in 95% TFA solution in the presence of 10 equiv-free Aoa as a carbonyl capture reagent that could prevent the reaction of the peptide with any carbonyl derivative. The crude product was purified by RP-HPLC, and the solvent was evaporated, followed by direct ligation to daunomycin (Dau) in 0.2 M NaOAc solution at pH 5. This procedure proved to be very efficient to prepare oxime-linked Dau-peptide conjugates."
REF00295	PDC_00133	Breast cancer	Female BALB/c mice murine 4T1 breast cancer cells xenograft tumor models.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	83%	%	.	.	.	.	Breast cancer 	Murine 4T1 breast cancer cell	.	.	15 days	.	.	"Given the potent effects of DP-sHDL in boosting anti-tumor immunity and relieving immunosuppressive microenvironment, its efficacy in treating TNBC model mice was evaluated. Through a 3-dose regime, DP-sHDL inhibited the growth of tumors by 84% and significantly reduced tumor burden. In contrast, DOX was less effective and caused a progressive decline in body weight. Further biochemical assays revealed that the levels of AST, CREA, CK and LDH in DOX-treated mice were significantly higher than those receiving PBS. Accordingly, inflammatory cell infiltration, cell necrosis and local swelling were observed in the heart, liver and kidneys, respectively, in the DOX-injection group. With the same regime, no visible damage was monitored in the major organs in DP-sHDL group. Based on these findings, the long-term efficacy of D-sHDL, P-sHDL and DP-sHDL were further evaluated. DP-sHDL retarded the tumor growth, and prolonged the median survival time (MST) from 18 days (PBS-treated mice) to 35 days, without body weight loss. These results proved that DP-sHDL could reduce the toxicity of DOX and effectively inhibit tumor growth."	"Herein, we report a dual-functional sHDL (DP-sHDL) that is co-assembled from DOX-ApoA1 mimetic peptide conjugate, PSB-603 (an A2BR inhibitor), phospholipid and cholesterol oleate (CO) through a microfluidic-based methodology. We expect that DP-sHDL could accumulate in tumor, where they can target cancerous cells, CAF and tumor-associated macrophages (TAMs). The DOX would induce the ICD of cancer cells and promote DC maturation and T lymphocyte infiltration and activity. PSB-603 is expected to block the A2BR, which would down-regulate CD73 and thus ADO, leading to a decrease in the intratumoral densities of several immunosuppressive cells. By simultaneously activating anti-tumor immunity and relieving immunosuppressive microenvironment, DP-sHDL may inhibit TNBC tumor growth and prolong the survival of animals, which could be further improved when used in combination with an immune checkpoint inhibitor."
REF00294	PDC_00111	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.9 &plusmn; 0.6 &micro;M	&micro;M	.	.	.	.	Melanoma	B16 cell	.	.	24 h	.	MTT assay	"In vitro studies of the antiproliferative effect showed that melanoma-targeting Dau-conjugates have significantly higher efficacy on B16 murine melanoma cell lines in comparison to human melanoma cell lines (A2058, M24, and WM983B). The IC50 values were detected between 2 and 2.9 &mu;M on B16 cells, where the highest activity was detected in the case of conjugate Conj3, followed by Conj2 and Conj1. Moreover, the relative potencies of conjugates to free Dau were also calculated as independent values from cell lines. A higher value of relative potency indicated the elevated targeting capacity of the conjugate on particular cell lines. Considering relative potencies, the best targeting capacity was shown to be Conj3 on all four cell lines, followed by Conj2 and Conj1. The highest antitumor activity of Conj3 on cells can be explained by the presence of two Dau molecules in this conjugate in comparison with Conj2 and Conj1, which contain only one drug molecule."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00111	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.8 &plusmn; 5.4 &micro;M	&micro;M	.	.	.	.	Melanoma	A2058 cell	.	.	24 h	.	MTT assay	"In vitro studies of the antiproliferative effect showed that melanoma-targeting Dau-conjugates have significantly higher efficacy on B16 murine melanoma cell lines in comparison to human melanoma cell lines (A2058, M24, and WM983B). The IC50 values were detected between 2 and 2.9 &mu;M on B16 cells, where the highest activity was detected in the case of conjugate Conj3, followed by Conj2 and Conj1. Moreover, the relative potencies of conjugates to free Dau were also calculated as independent values from cell lines. A higher value of relative potency indicated the elevated targeting capacity of the conjugate on particular cell lines. Considering relative potencies, the best targeting capacity was shown to be Conj3 on all four cell lines, followed by Conj2 and Conj1. The highest antitumor activity of Conj3 on cells can be explained by the presence of two Dau molecules in this conjugate in comparison with Conj2 and Conj1, which contain only one drug molecule."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00111	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	12.8 &plusmn; 1.6 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	M24 cell	.	.	24 h	.	MTT assay	"In vitro studies of the antiproliferative effect showed that melanoma-targeting Dau-conjugates have significantly higher efficacy on B16 murine melanoma cell lines in comparison to human melanoma cell lines (A2058, M24, and WM983B). The IC50 values were detected between 2 and 2.9 &mu;M on B16 cells, where the highest activity was detected in the case of conjugate Conj3, followed by Conj2 and Conj1. Moreover, the relative potencies of conjugates to free Dau were also calculated as independent values from cell lines. A higher value of relative potency indicated the elevated targeting capacity of the conjugate on particular cell lines. Considering relative potencies, the best targeting capacity was shown to be Conj3 on all four cell lines, followed by Conj2 and Conj1. The highest antitumor activity of Conj3 on cells can be explained by the presence of two Dau molecules in this conjugate in comparison with Conj2 and Conj1, which contain only one drug molecule."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00111	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.9 &plusmn; 1.5 &micro;M	&micro;M	.	.	.	.	Melanoma	WM983B cell	.	.	24 h	.	MTT assay	"In vitro studies of the antiproliferative effect showed that melanoma-targeting Dau-conjugates have significantly higher efficacy on B16 murine melanoma cell lines in comparison to human melanoma cell lines (A2058, M24, and WM983B). The IC50 values were detected between 2 and 2.9 &mu;M on B16 cells, where the highest activity was detected in the case of conjugate Conj3, followed by Conj2 and Conj1. Moreover, the relative potencies of conjugates to free Dau were also calculated as independent values from cell lines. A higher value of relative potency indicated the elevated targeting capacity of the conjugate on particular cell lines. Considering relative potencies, the best targeting capacity was shown to be Conj3 on all four cell lines, followed by Conj2 and Conj1. The highest antitumor activity of Conj3 on cells can be explained by the presence of two Dau molecules in this conjugate in comparison with Conj2 and Conj1, which contain only one drug molecule."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00056	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.8 &plusmn; 0.7 &micro;M	&micro;M	.	.	.	.	Melanoma	B16 cell	.	.	24 h	.	MTT assay	"In vitro studies of the antiproliferative effect showed that melanoma-targeting Dau-conjugates have significantly higher efficacy on B16 murine melanoma cell lines in comparison to human melanoma cell lines (A2058, M24, and WM983B). The IC50 values were detected between 2 and 2.9 &mu;M on B16 cells, where the highest activity was detected in the case of conjugate Conj3, followed by Conj2 and Conj1. Moreover, the relative potencies of conjugates to free Dau were also calculated as independent values from cell lines. A higher value of relative potency indicated the elevated targeting capacity of the conjugate on particular cell lines. Considering relative potencies, the best targeting capacity was shown to be Conj3 on all four cell lines, followed by Conj2 and Conj1. The highest antitumor activity of Conj3 on cells can be explained by the presence of two Dau molecules in this conjugate in comparison with Conj2 and Conj1, which contain only one drug molecule."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00056	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.2 &plusmn; 0.4 &micro;M	&micro;M	.	.	.	.	Melanoma	A2058 cell	.	.	24 h	.	MTT assay	"In vitro studies of the antiproliferative effect showed that melanoma-targeting Dau-conjugates have significantly higher efficacy on B16 murine melanoma cell lines in comparison to human melanoma cell lines (A2058, M24, and WM983B). The IC50 values were detected between 2 and 2.9 &mu;M on B16 cells, where the highest activity was detected in the case of conjugate Conj3, followed by Conj2 and Conj1. Moreover, the relative potencies of conjugates to free Dau were also calculated as independent values from cell lines. A higher value of relative potency indicated the elevated targeting capacity of the conjugate on particular cell lines. Considering relative potencies, the best targeting capacity was shown to be Conj3 on all four cell lines, followed by Conj2 and Conj1. The highest antitumor activity of Conj3 on cells can be explained by the presence of two Dau molecules in this conjugate in comparison with Conj2 and Conj1, which contain only one drug molecule."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00056	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11.5 &plusmn; 0.4 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	M24 cell	.	.	24 h	.	MTT assay	"In vitro studies of the antiproliferative effect showed that melanoma-targeting Dau-conjugates have significantly higher efficacy on B16 murine melanoma cell lines in comparison to human melanoma cell lines (A2058, M24, and WM983B). The IC50 values were detected between 2 and 2.9 &mu;M on B16 cells, where the highest activity was detected in the case of conjugate Conj3, followed by Conj2 and Conj1. Moreover, the relative potencies of conjugates to free Dau were also calculated as independent values from cell lines. A higher value of relative potency indicated the elevated targeting capacity of the conjugate on particular cell lines. Considering relative potencies, the best targeting capacity was shown to be Conj3 on all four cell lines, followed by Conj2 and Conj1. The highest antitumor activity of Conj3 on cells can be explained by the presence of two Dau molecules in this conjugate in comparison with Conj2 and Conj1, which contain only one drug molecule."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00056	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.9 &plusmn; 0.7 &micro;M	&micro;M	.	.	.	.	Melanoma	WM983B cell	.	.	24 h	.	MTT assay	"In vitro studies of the antiproliferative effect showed that melanoma-targeting Dau-conjugates have significantly higher efficacy on B16 murine melanoma cell lines in comparison to human melanoma cell lines (A2058, M24, and WM983B). The IC50 values were detected between 2 and 2.9 &mu;M on B16 cells, where the highest activity was detected in the case of conjugate Conj3, followed by Conj2 and Conj1. Moreover, the relative potencies of conjugates to free Dau were also calculated as independent values from cell lines. A higher value of relative potency indicated the elevated targeting capacity of the conjugate on particular cell lines. Considering relative potencies, the best targeting capacity was shown to be Conj3 on all four cell lines, followed by Conj2 and Conj1. The highest antitumor activity of Conj3 on cells can be explained by the presence of two Dau molecules in this conjugate in comparison with Conj2 and Conj1, which contain only one drug molecule."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00110	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.0 &plusmn; 0.7 &micro;M	&micro;M	.	.	.	.	Melanoma	B16 cell	.	.	24 h	.	MTT assay	"In vitro studies of the antiproliferative effect showed that melanoma-targeting Dau-conjugates have significantly higher efficacy on B16 murine melanoma cell lines in comparison to human melanoma cell lines (A2058, M24, and WM983B). The IC50 values were detected between 2 and 2.9 &mu;M on B16 cells, where the highest activity was detected in the case of conjugate Conj3, followed by Conj2 and Conj1. Moreover, the relative potencies of conjugates to free Dau were also calculated as independent values from cell lines. A higher value of relative potency indicated the elevated targeting capacity of the conjugate on particular cell lines. Considering relative potencies, the best targeting capacity was shown to be Conj3 on all four cell lines, followed by Conj2 and Conj1. The highest antitumor activity of Conj3 on cells can be explained by the presence of two Dau molecules in this conjugate in comparison with Conj2 and Conj1, which contain only one drug molecule."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00110	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.0 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	Melanoma	A2058 cell	.	.	24 h	.	MTT assay	"In vitro studies of the antiproliferative effect showed that melanoma-targeting Dau-conjugates have significantly higher efficacy on B16 murine melanoma cell lines in comparison to human melanoma cell lines (A2058, M24, and WM983B). The IC50 values were detected between 2 and 2.9 &mu;M on B16 cells, where the highest activity was detected in the case of conjugate Conj3, followed by Conj2 and Conj1. Moreover, the relative potencies of conjugates to free Dau were also calculated as independent values from cell lines. A higher value of relative potency indicated the elevated targeting capacity of the conjugate on particular cell lines. Considering relative potencies, the best targeting capacity was shown to be Conj3 on all four cell lines, followed by Conj2 and Conj1. The highest antitumor activity of Conj3 on cells can be explained by the presence of two Dau molecules in this conjugate in comparison with Conj2 and Conj1, which contain only one drug molecule."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00110	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11.0 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	M24 cell	.	.	24 h	.	MTT assay	"In vitro studies of the antiproliferative effect showed that melanoma-targeting Dau-conjugates have significantly higher efficacy on B16 murine melanoma cell lines in comparison to human melanoma cell lines (A2058, M24, and WM983B). The IC50 values were detected between 2 and 2.9 &mu;M on B16 cells, where the highest activity was detected in the case of conjugate Conj3, followed by Conj2 and Conj1. Moreover, the relative potencies of conjugates to free Dau were also calculated as independent values from cell lines. A higher value of relative potency indicated the elevated targeting capacity of the conjugate on particular cell lines. Considering relative potencies, the best targeting capacity was shown to be Conj3 on all four cell lines, followed by Conj2 and Conj1. The highest antitumor activity of Conj3 on cells can be explained by the presence of two Dau molecules in this conjugate in comparison with Conj2 and Conj1, which contain only one drug molecule."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00110	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.6 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Melanoma	WM983B cell	.	.	24 h	.	MTT assay	"In vitro studies of the antiproliferative effect showed that melanoma-targeting Dau-conjugates have significantly higher efficacy on B16 murine melanoma cell lines in comparison to human melanoma cell lines (A2058, M24, and WM983B). The IC50 values were detected between 2 and 2.9 &mu;M on B16 cells, where the highest activity was detected in the case of conjugate Conj3, followed by Conj2 and Conj1. Moreover, the relative potencies of conjugates to free Dau were also calculated as independent values from cell lines. A higher value of relative potency indicated the elevated targeting capacity of the conjugate on particular cell lines. Considering relative potencies, the best targeting capacity was shown to be Conj3 on all four cell lines, followed by Conj2 and Conj1. The highest antitumor activity of Conj3 on cells can be explained by the presence of two Dau molecules in this conjugate in comparison with Conj2 and Conj1, which contain only one drug molecule."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00056	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.51 &plusmn; 0.06 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	OCM-1 cell	.	.	24 h	.	MTT assay	"The in vitro cytostatic effects of Dau--MSH conjugates were compared with the PrestoBlue assay, which has a higher specificity and efficacy that of the previously used MTT assay, using the same six human melanoma cell lines used in the real-time qPCR assay. According to our results, free daunomycin exhibited the lowest IC50 values, and therefore the highest cytostatic effect, due to the fact that free daunomycin passively diffuses into cells. Our Dau--MSH conjugates showed similar trends in the effectiveness of the tested cell lines. Conj2 and Conj4 resulted in IC50 values in the low uM range. A calculation of the targeting indices showed that compound Conj2 had an over 2-times higher targeting efficiency in most cell lines compared to the A2058 cell line. Interestingly, WM983A showed the lowest TI among the high-MC1R-expressing cell lines compared to A2058, and WM983B exhibited high TI regardless of the relatively low MC1R expression on the mRNA level. In the case of Conj4, the treatment resulted in the highest TIs with OCM-1 and WM983B cell lines."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00056	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.39 &plusmn; 0.06 &micro;M	&micro;M	.	.	.	.	Cutaneous melanoma	OCM-3 cell	.	.	24 h	.	MTT assay	"The in vitro cytostatic effects of Dau--MSH conjugates were compared with the PrestoBlue assay, which has a higher specificity and efficacy that of the previously used MTT assay, using the same six human melanoma cell lines used in the real-time qPCR assay. According to our results, free daunomycin exhibited the lowest IC50 values, and therefore the highest cytostatic effect, due to the fact that free daunomycin passively diffuses into cells. Our Dau--MSH conjugates showed similar trends in the effectiveness of the tested cell lines. Conj2 and Conj4 resulted in IC50 values in the low uM range. A calculation of the targeting indices showed that compound Conj2 had an over 2-times higher targeting efficiency in most cell lines compared to the A2058 cell line. Interestingly, WM983A showed the lowest TI among the high-MC1R-expressing cell lines compared to A2058, and WM983B exhibited high TI regardless of the relatively low MC1R expression on the mRNA level. In the case of Conj4, the treatment resulted in the highest TIs with OCM-1 and WM983B cell lines."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00056	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.13 &plusmn; 0.09 &micro;M	&micro;M	.	.	.	.	Melanoma	SK-MEL-202 cell	.	.	24 h	.	MTT assay	"The in vitro cytostatic effects of Dau--MSH conjugates were compared with the PrestoBlue assay, which has a higher specificity and efficacy that of the previously used MTT assay, using the same six human melanoma cell lines used in the real-time qPCR assay. According to our results, free daunomycin exhibited the lowest IC50 values, and therefore the highest cytostatic effect, due to the fact that free daunomycin passively diffuses into cells. Our Dau--MSH conjugates showed similar trends in the effectiveness of the tested cell lines. Conj2 and Conj4 resulted in IC50 values in the low uM range. A calculation of the targeting indices showed that compound Conj2 had an over 2-times higher targeting efficiency in most cell lines compared to the A2058 cell line. Interestingly, WM983A showed the lowest TI among the high-MC1R-expressing cell lines compared to A2058, and WM983B exhibited high TI regardless of the relatively low MC1R expression on the mRNA level. In the case of Conj4, the treatment resulted in the highest TIs with OCM-1 and WM983B cell lines."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00056	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.79 &plusmn; 0.05 &micro;M	&micro;M	.	.	.	.	Melanoma	WM983A cell	.	.	24 h	.	MTT assay	"The in vitro cytostatic effects of Dau--MSH conjugates were compared with the PrestoBlue assay, which has a higher specificity and efficacy that of the previously used MTT assay, using the same six human melanoma cell lines used in the real-time qPCR assay. According to our results, free daunomycin exhibited the lowest IC50 values, and therefore the highest cytostatic effect, due to the fact that free daunomycin passively diffuses into cells. Our Dau--MSH conjugates showed similar trends in the effectiveness of the tested cell lines. Conj2 and Conj4 resulted in IC50 values in the low uM range. A calculation of the targeting indices showed that compound Conj2 had an over 2-times higher targeting efficiency in most cell lines compared to the A2058 cell line. Interestingly, WM983A showed the lowest TI among the high-MC1R-expressing cell lines compared to A2058, and WM983B exhibited high TI regardless of the relatively low MC1R expression on the mRNA level. In the case of Conj4, the treatment resulted in the highest TIs with OCM-1 and WM983B cell lines."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00056	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.00 &plusmn; 0.00 &micro;M	&micro;M	.	.	.	.	Melanoma	WM983B cell	.	.	24 h	.	MTT assay	"The in vitro cytostatic effects of Dau--MSH conjugates were compared with the PrestoBlue assay, which has a higher specificity and efficacy that of the previously used MTT assay, using the same six human melanoma cell lines used in the real-time qPCR assay. According to our results, free daunomycin exhibited the lowest IC50 values, and therefore the highest cytostatic effect, due to the fact that free daunomycin passively diffuses into cells. Our Dau--MSH conjugates showed similar trends in the effectiveness of the tested cell lines. Conj2 and Conj4 resulted in IC50 values in the low uM range. A calculation of the targeting indices showed that compound Conj2 had an over 2-times higher targeting efficiency in most cell lines compared to the A2058 cell line. Interestingly, WM983A showed the lowest TI among the high-MC1R-expressing cell lines compared to A2058, and WM983B exhibited high TI regardless of the relatively low MC1R expression on the mRNA level. In the case of Conj4, the treatment resulted in the highest TIs with OCM-1 and WM983B cell lines."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00056	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.95 &plusmn; 0.12 &micro;M	&micro;M	.	.	.	.	Melanoma	A2058 cell	.	.	24 h	.	MTT assay	"The in vitro cytostatic effects of Dau--MSH conjugates were compared with the PrestoBlue assay, which has a higher specificity and efficacy that of the previously used MTT assay, using the same six human melanoma cell lines used in the real-time qPCR assay. According to our results, free daunomycin exhibited the lowest IC50 values, and therefore the highest cytostatic effect, due to the fact that free daunomycin passively diffuses into cells. Our Dau--MSH conjugates showed similar trends in the effectiveness of the tested cell lines. Conj2 and Conj4 resulted in IC50 values in the low uM range. A calculation of the targeting indices showed that compound Conj2 had an over 2-times higher targeting efficiency in most cell lines compared to the A2058 cell line. Interestingly, WM983A showed the lowest TI among the high-MC1R-expressing cell lines compared to A2058, and WM983B exhibited high TI regardless of the relatively low MC1R expression on the mRNA level. In the case of Conj4, the treatment resulted in the highest TIs with OCM-1 and WM983B cell lines."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00055	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	29.68 &plusmn; 0.06 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	OCM-1 cell	.	.	24 h	.	MTT assay	"The in vitro cytostatic effects of Dau--MSH conjugates were compared with the PrestoBlue assay, which has a higher specificity and efficacy that of the previously used MTT assay, using the same six human melanoma cell lines used in the real-time qPCR assay. According to our results, free daunomycin exhibited the lowest IC50 values, and therefore the highest cytostatic effect, due to the fact that free daunomycin passively diffuses into cells. Our Dau--MSH conjugates showed similar trends in the effectiveness of the tested cell lines. Conj2 and Conj4 resulted in IC50 values in the low uM range. A calculation of the targeting indices showed that compound Conj2 had an over 2-times higher targeting efficiency in most cell lines compared to the A2058 cell line. Interestingly, WM983A showed the lowest TI among the high-MC1R-expressing cell lines compared to A2058, and WM983B exhibited high TI regardless of the relatively low MC1R expression on the mRNA level. In the case of Conj4, the treatment resulted in the highest TIs with OCM-1 and WM983B cell lines."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00055	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	25.47 &plusmn; 0.08 &micro;M	&micro;M	.	.	.	.	Cutaneous melanoma	OCM-3 cell	.	.	24 h	.	MTT assay	"The in vitro cytostatic effects of Dau--MSH conjugates were compared with the PrestoBlue assay, which has a higher specificity and efficacy that of the previously used MTT assay, using the same six human melanoma cell lines used in the real-time qPCR assay. According to our results, free daunomycin exhibited the lowest IC50 values, and therefore the highest cytostatic effect, due to the fact that free daunomycin passively diffuses into cells. Our Dau--MSH conjugates showed similar trends in the effectiveness of the tested cell lines. Conj2 and Conj4 resulted in IC50 values in the low uM range. A calculation of the targeting indices showed that compound Conj2 had an over 2-times higher targeting efficiency in most cell lines compared to the A2058 cell line. Interestingly, WM983A showed the lowest TI among the high-MC1R-expressing cell lines compared to A2058, and WM983B exhibited high TI regardless of the relatively low MC1R expression on the mRNA level. In the case of Conj4, the treatment resulted in the highest TIs with OCM-1 and WM983B cell lines."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00055	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.06 &plusmn; 0.10 &micro;M	&micro;M	.	.	.	.	Melanoma	SK-MEL-202 cell	.	.	24 h	.	MTT assay	"The in vitro cytostatic effects of Dau--MSH conjugates were compared with the PrestoBlue assay, which has a higher specificity and efficacy that of the previously used MTT assay, using the same six human melanoma cell lines used in the real-time qPCR assay. According to our results, free daunomycin exhibited the lowest IC50 values, and therefore the highest cytostatic effect, due to the fact that free daunomycin passively diffuses into cells. Our Dau--MSH conjugates showed similar trends in the effectiveness of the tested cell lines. Conj2 and Conj4 resulted in IC50 values in the low uM range. A calculation of the targeting indices showed that compound Conj2 had an over 2-times higher targeting efficiency in most cell lines compared to the A2058 cell line. Interestingly, WM983A showed the lowest TI among the high-MC1R-expressing cell lines compared to A2058, and WM983B exhibited high TI regardless of the relatively low MC1R expression on the mRNA level. In the case of Conj4, the treatment resulted in the highest TIs with OCM-1 and WM983B cell lines."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00055	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	13.50 &plusmn; 0.06 &micro;M	&micro;M	.	.	.	.	Melanoma	WM983A cell	.	.	24 h	.	MTT assay	"The in vitro cytostatic effects of Dau--MSH conjugates were compared with the PrestoBlue assay, which has a higher specificity and efficacy that of the previously used MTT assay, using the same six human melanoma cell lines used in the real-time qPCR assay. According to our results, free daunomycin exhibited the lowest IC50 values, and therefore the highest cytostatic effect, due to the fact that free daunomycin passively diffuses into cells. Our Dau--MSH conjugates showed similar trends in the effectiveness of the tested cell lines. Conj2 and Conj4 resulted in IC50 values in the low uM range. A calculation of the targeting indices showed that compound Conj2 had an over 2-times higher targeting efficiency in most cell lines compared to the A2058 cell line. Interestingly, WM983A showed the lowest TI among the high-MC1R-expressing cell lines compared to A2058, and WM983B exhibited high TI regardless of the relatively low MC1R expression on the mRNA level. In the case of Conj4, the treatment resulted in the highest TIs with OCM-1 and WM983B cell lines."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00055	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.18 &plusmn; 0.06 &micro;M	&micro;M	.	.	.	.	Melanoma	WM983B cell	.	.	24 h	.	MTT assay	"The in vitro cytostatic effects of Dau--MSH conjugates were compared with the PrestoBlue assay, which has a higher specificity and efficacy that of the previously used MTT assay, using the same six human melanoma cell lines used in the real-time qPCR assay. According to our results, free daunomycin exhibited the lowest IC50 values, and therefore the highest cytostatic effect, due to the fact that free daunomycin passively diffuses into cells. Our Dau--MSH conjugates showed similar trends in the effectiveness of the tested cell lines. Conj2 and Conj4 resulted in IC50 values in the low uM range. A calculation of the targeting indices showed that compound Conj2 had an over 2-times higher targeting efficiency in most cell lines compared to the A2058 cell line. Interestingly, WM983A showed the lowest TI among the high-MC1R-expressing cell lines compared to A2058, and WM983B exhibited high TI regardless of the relatively low MC1R expression on the mRNA level. In the case of Conj4, the treatment resulted in the highest TIs with OCM-1 and WM983B cell lines."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00294	PDC_00055	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.15 &plusmn; 0.07 &micro;M	&micro;M	.	.	.	.	Melanoma	A2058 cell	.	.	24 h	.	MTT assay	"The in vitro cytostatic effects of Dau--MSH conjugates were compared with the PrestoBlue assay, which has a higher specificity and efficacy that of the previously used MTT assay, using the same six human melanoma cell lines used in the real-time qPCR assay. According to our results, free daunomycin exhibited the lowest IC50 values, and therefore the highest cytostatic effect, due to the fact that free daunomycin passively diffuses into cells. Our Dau--MSH conjugates showed similar trends in the effectiveness of the tested cell lines. Conj2 and Conj4 resulted in IC50 values in the low uM range. A calculation of the targeting indices showed that compound Conj2 had an over 2-times higher targeting efficiency in most cell lines compared to the A2058 cell line. Interestingly, WM983A showed the lowest TI among the high-MC1R-expressing cell lines compared to A2058, and WM983B exhibited high TI regardless of the relatively low MC1R expression on the mRNA level. In the case of Conj4, the treatment resulted in the highest TIs with OCM-1 and WM983B cell lines."	"In this study, the native sequence of -MSH was used, in which Met was replaced by Nle (SYSNleEHFRWGKPV). Daunomycin was attached to the amino functional groups via non-cleavable oxime linkage. These types of conjugates have many excellent properties to study and compare the bioactivity of the compounds. One of the developed conjugates contained drug molecules on both conjugation site (N-terminal and the side chain of Lys). The two additional conjugates were modified by the drug, either on theN-terminus or on the Lys side chain. The in vitro cytostatic effect on mouse melanoma cells did not show any significant differences among them. However, results indicated that the conjugates with Dau on the side chain of Lys could enter the cells more rapidly and efficiently. In contrast, the in vivo tumor growth inhibition was the most pronounced in the case of Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2(Conj2). It is worth mentioning that the dose was normalized to Dau content, thus the injected dose ofConj3was half that ofConj 2. Nevertheless,Conj2, with one molecule of the drug, might be superior to the conjugate containing two molecules of daunomycin. The higher tumor growth inhibition effect ofConj2overConj1where the Dau is connected to theN-terminus, confirms our previous results with Dau-GnRH-III (Glp-His-Trp-Lys(Bu)-His-Asp-Trp-Lys(Dau=Aoa)-Pro-Gly-NH2), suggesting that H-Lys(Dau=Aoa)-OH can release easily from this position by the dipeptidyl-peptidase activity of cathepsin B."
REF00293	PDC_00346	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	70.07nM	nM	.	.	.	.	Glioblastoma	U-87MG cell	.	.	72 h	.	XTT assay	"Further, IC50values of SN-38 and T7-SN-38 on U87MG cells at 72 h were determined. An estimated IC50value of 26.41nM was obtained for SN-38, which was considerably lower than an IC50value of 70.07nM obtained for the T7-SN-38 conjugate. These IC50data confirm the greater cytotoxicity of the pure drug compared to the conjugate at 72 h (p< 0.05)."	"In the present work, the cytotoxic drug SN-38 is coupled to the tumor-targeting T7 peptide via a cathepsin B cleavable VA peptide linker. This ensures that the drug remains covalently bound until it reaches the intended site of action, where Cat B is overexpressed to release the drug. Within this framework, our research pursuits entail the synthesis and characterization of a T7-SN-38-targeted drug conjugate using strain-promoted azide-alkyne cycloaddition (SPAAC). Our investigation extended to evaluating the cellular uptake and assessing the cytotoxicity of the drug conjugate in U87MG glioblastoma cells."
REF00291	PDC_00254	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	8 &micro;g/mL	&micro;g/mL	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus infection strain	.	.	18 h	.	MIC assay	"To verify whether Omi-hyd-Dex@HA NPs inherited the antimicrobial activity of omiganan, the MICs were tested by the standardized agar doubling-dilution method as shown in Table 1. Omi-hyd-Dex@HA NPs and free omiganan showed similar extended broad-spectrum antibacterial activity for G+ bacteria, G- bacteria and fungi pathogens, including drug-sensitive strains (S. aureus, P. aeruginosa, K.P., Candida albicans) and drug-resistant strains (MRSA, MDR-K.P.). The MICs of Omi-hyd-Dex@HA NPs showed none or only a one-fold increase compared with the free Omiganan-NHNH2 group. In addition, free Dex did not show any antimicrobial activity for the tested pathogens, indicating that Dex moieties of Omi-hyd-Dex@HA NPs did not contribute to the bacterial killing effect. In contrast, vancomycin, as a standard drug regimen for drug-resistant G+ strains, showed inefficacious for G- strains and fungus. Similar results were also observed in oxacillin-treated groups. Therefore, Omi-hyd-Dex@HA NPs retained the broad-spectrum antimicrobial activity of omiganan."	"To minimize the toxic side effect of omiganan and optimize its anti-inflammatory capability, we designed an IMEs-responsive self-delivery nanosystem consisting of omiganan, an anti-inflammatory agent, and natural polysaccharide to achieve on-demand degradation and responsive drug release. Based on the cationic hydrophilic fragments on omiganan, we chose dexamethasone (Dex, a hydrophobic anti-inflammatory drug) to link with this peptide via a hydrazone bond to construct an amphiphilic conjugate (Omi-hyd-Dex). With the assistance of PLGA, this conjugate could self-assemble into nanoparticles (Omi-hyd-Dex NPs) in an aqueous solution without introducing any other hazardous materials. Then, the negatively-charged hyaluronic acid (HA, a natural ligand of ICAM-1 and CD44) was used to coat Omi-hyd-Dex NPs to form a core-shell structural formulation (Omi-hyd-Dex@HA NPs). This HA coating could not only eliminate the hemolytic activity of omiganan to reduce side effects but also act as the IMEs targeting molecule through interaction with intercellular adhesion molecule-1 (ICAM-1) on inflamed endothelial cells. After entering IMEs, the HA coating would be degraded and detached to expose the cationic surface of the Omi-hyd-Dex core and enable it to accumulate in IMEs. Meanwhile, the hydrazone bond between omiganan and Dex could be cleaved in response to the acidic condition of IMEs, thereby releasing the cationic peptide and anti-inflammatory agent that would concurrently inhibit the infection and inflammation precisely."
REF00291	PDC_00254	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	16 &micro;g/mL	&micro;g/mL	.	.	.	.	Multiple-resistant Staphylococcus aureus infection	Multiple-resistant staphylococcus aureus infection strain	.	.	18 h	.	MIC assay	"To verify whether Omi-hyd-Dex@HA NPs inherited the antimicrobial activity of omiganan, the MICs were tested by the standardized agar doubling-dilution method as shown in Table 1. Omi-hyd-Dex@HA NPs and free omiganan showed similar extended broad-spectrum antibacterial activity for G+ bacteria, G- bacteria and fungi pathogens, including drug-sensitive strains (S. aureus, P. aeruginosa, K.P., Candida albicans) and drug-resistant strains (MRSA, MDR-K.P.). The MICs of Omi-hyd-Dex@HA NPs showed none or only a one-fold increase compared with the free Omiganan-NHNH2 group. In addition, free Dex did not show any antimicrobial activity for the tested pathogens, indicating that Dex moieties of Omi-hyd-Dex@HA NPs did not contribute to the bacterial killing effect. In contrast, vancomycin, as a standard drug regimen for drug-resistant G+ strains, showed inefficacious for G- strains and fungus. Similar results were also observed in oxacillin-treated groups. Therefore, Omi-hyd-Dex@HA NPs retained the broad-spectrum antimicrobial activity of omiganan."	"To minimize the toxic side effect of omiganan and optimize its anti-inflammatory capability, we designed an IMEs-responsive self-delivery nanosystem consisting of omiganan, an anti-inflammatory agent, and natural polysaccharide to achieve on-demand degradation and responsive drug release. Based on the cationic hydrophilic fragments on omiganan, we chose dexamethasone (Dex, a hydrophobic anti-inflammatory drug) to link with this peptide via a hydrazone bond to construct an amphiphilic conjugate (Omi-hyd-Dex). With the assistance of PLGA, this conjugate could self-assemble into nanoparticles (Omi-hyd-Dex NPs) in an aqueous solution without introducing any other hazardous materials. Then, the negatively-charged hyaluronic acid (HA, a natural ligand of ICAM-1 and CD44) was used to coat Omi-hyd-Dex NPs to form a core-shell structural formulation (Omi-hyd-Dex@HA NPs). This HA coating could not only eliminate the hemolytic activity of omiganan to reduce side effects but also act as the IMEs targeting molecule through interaction with intercellular adhesion molecule-1 (ICAM-1) on inflamed endothelial cells. After entering IMEs, the HA coating would be degraded and detached to expose the cationic surface of the Omi-hyd-Dex core and enable it to accumulate in IMEs. Meanwhile, the hydrazone bond between omiganan and Dex could be cleaved in response to the acidic condition of IMEs, thereby releasing the cationic peptide and anti-inflammatory agent that would concurrently inhibit the infection and inflammation precisely."
REF00291	PDC_00254	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	32 &micro;g/mL	&micro;g/mL	.	.	.	.	Pseudomonas aeruginosa strain infection	Pseudomonas aeruginosa strain	.	.	18 h	.	MIC assay	"To verify whether Omi-hyd-Dex@HA NPs inherited the antimicrobial activity of omiganan, the MICs were tested by the standardized agar doubling-dilution method as shown in Table 1. Omi-hyd-Dex@HA NPs and free omiganan showed similar extended broad-spectrum antibacterial activity for G+ bacteria, G- bacteria and fungi pathogens, including drug-sensitive strains (S. aureus, P. aeruginosa, K.P., Candida albicans) and drug-resistant strains (MRSA, MDR-K.P.). The MICs of Omi-hyd-Dex@HA NPs showed none or only a one-fold increase compared with the free Omiganan-NHNH2 group. In addition, free Dex did not show any antimicrobial activity for the tested pathogens, indicating that Dex moieties of Omi-hyd-Dex@HA NPs did not contribute to the bacterial killing effect. In contrast, vancomycin, as a standard drug regimen for drug-resistant G+ strains, showed inefficacious for G- strains and fungus. Similar results were also observed in oxacillin-treated groups. Therefore, Omi-hyd-Dex@HA NPs retained the broad-spectrum antimicrobial activity of omiganan."	"To minimize the toxic side effect of omiganan and optimize its anti-inflammatory capability, we designed an IMEs-responsive self-delivery nanosystem consisting of omiganan, an anti-inflammatory agent, and natural polysaccharide to achieve on-demand degradation and responsive drug release. Based on the cationic hydrophilic fragments on omiganan, we chose dexamethasone (Dex, a hydrophobic anti-inflammatory drug) to link with this peptide via a hydrazone bond to construct an amphiphilic conjugate (Omi-hyd-Dex). With the assistance of PLGA, this conjugate could self-assemble into nanoparticles (Omi-hyd-Dex NPs) in an aqueous solution without introducing any other hazardous materials. Then, the negatively-charged hyaluronic acid (HA, a natural ligand of ICAM-1 and CD44) was used to coat Omi-hyd-Dex NPs to form a core-shell structural formulation (Omi-hyd-Dex@HA NPs). This HA coating could not only eliminate the hemolytic activity of omiganan to reduce side effects but also act as the IMEs targeting molecule through interaction with intercellular adhesion molecule-1 (ICAM-1) on inflamed endothelial cells. After entering IMEs, the HA coating would be degraded and detached to expose the cationic surface of the Omi-hyd-Dex core and enable it to accumulate in IMEs. Meanwhile, the hydrazone bond between omiganan and Dex could be cleaved in response to the acidic condition of IMEs, thereby releasing the cationic peptide and anti-inflammatory agent that would concurrently inhibit the infection and inflammation precisely."
REF00291	PDC_00254	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	16 &micro;g/mL	&micro;g/mL	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae strain	.	.	18 h	.	MIC assay	"To verify whether Omi-hyd-Dex@HA NPs inherited the antimicrobial activity of omiganan, the MICs were tested by the standardized agar doubling-dilution method as shown in Table 1. Omi-hyd-Dex@HA NPs and free omiganan showed similar extended broad-spectrum antibacterial activity for G+ bacteria, G- bacteria and fungi pathogens, including drug-sensitive strains (S. aureus, P. aeruginosa, K.P., Candida albicans) and drug-resistant strains (MRSA, MDR-K.P.). The MICs of Omi-hyd-Dex@HA NPs showed none or only a one-fold increase compared with the free Omiganan-NHNH2 group. In addition, free Dex did not show any antimicrobial activity for the tested pathogens, indicating that Dex moieties of Omi-hyd-Dex@HA NPs did not contribute to the bacterial killing effect. In contrast, vancomycin, as a standard drug regimen for drug-resistant G+ strains, showed inefficacious for G- strains and fungus. Similar results were also observed in oxacillin-treated groups. Therefore, Omi-hyd-Dex@HA NPs retained the broad-spectrum antimicrobial activity of omiganan."	"To minimize the toxic side effect of omiganan and optimize its anti-inflammatory capability, we designed an IMEs-responsive self-delivery nanosystem consisting of omiganan, an anti-inflammatory agent, and natural polysaccharide to achieve on-demand degradation and responsive drug release. Based on the cationic hydrophilic fragments on omiganan, we chose dexamethasone (Dex, a hydrophobic anti-inflammatory drug) to link with this peptide via a hydrazone bond to construct an amphiphilic conjugate (Omi-hyd-Dex). With the assistance of PLGA, this conjugate could self-assemble into nanoparticles (Omi-hyd-Dex NPs) in an aqueous solution without introducing any other hazardous materials. Then, the negatively-charged hyaluronic acid (HA, a natural ligand of ICAM-1 and CD44) was used to coat Omi-hyd-Dex NPs to form a core-shell structural formulation (Omi-hyd-Dex@HA NPs). This HA coating could not only eliminate the hemolytic activity of omiganan to reduce side effects but also act as the IMEs targeting molecule through interaction with intercellular adhesion molecule-1 (ICAM-1) on inflamed endothelial cells. After entering IMEs, the HA coating would be degraded and detached to expose the cationic surface of the Omi-hyd-Dex core and enable it to accumulate in IMEs. Meanwhile, the hydrazone bond between omiganan and Dex could be cleaved in response to the acidic condition of IMEs, thereby releasing the cationic peptide and anti-inflammatory agent that would concurrently inhibit the infection and inflammation precisely."
REF00291	PDC_00254	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	16 &micro;g/mL	&micro;g/mL	.	.	.	.	Klebsiella pneumoniae infection	MDR Klebsiella pneumoniae strain	.	.	18 h	.	MIC assay	"To verify whether Omi-hyd-Dex@HA NPs inherited the antimicrobial activity of omiganan, the MICs were tested by the standardized agar doubling-dilution method as shown in Table 1. Omi-hyd-Dex@HA NPs and free omiganan showed similar extended broad-spectrum antibacterial activity for G+ bacteria, G- bacteria and fungi pathogens, including drug-sensitive strains (S. aureus, P. aeruginosa, K.P., Candida albicans) and drug-resistant strains (MRSA, MDR-K.P.). The MICs of Omi-hyd-Dex@HA NPs showed none or only a one-fold increase compared with the free Omiganan-NHNH2 group. In addition, free Dex did not show any antimicrobial activity for the tested pathogens, indicating that Dex moieties of Omi-hyd-Dex@HA NPs did not contribute to the bacterial killing effect. In contrast, vancomycin, as a standard drug regimen for drug-resistant G+ strains, showed inefficacious for G- strains and fungus. Similar results were also observed in oxacillin-treated groups. Therefore, Omi-hyd-Dex@HA NPs retained the broad-spectrum antimicrobial activity of omiganan."	"To minimize the toxic side effect of omiganan and optimize its anti-inflammatory capability, we designed an IMEs-responsive self-delivery nanosystem consisting of omiganan, an anti-inflammatory agent, and natural polysaccharide to achieve on-demand degradation and responsive drug release. Based on the cationic hydrophilic fragments on omiganan, we chose dexamethasone (Dex, a hydrophobic anti-inflammatory drug) to link with this peptide via a hydrazone bond to construct an amphiphilic conjugate (Omi-hyd-Dex). With the assistance of PLGA, this conjugate could self-assemble into nanoparticles (Omi-hyd-Dex NPs) in an aqueous solution without introducing any other hazardous materials. Then, the negatively-charged hyaluronic acid (HA, a natural ligand of ICAM-1 and CD44) was used to coat Omi-hyd-Dex NPs to form a core-shell structural formulation (Omi-hyd-Dex@HA NPs). This HA coating could not only eliminate the hemolytic activity of omiganan to reduce side effects but also act as the IMEs targeting molecule through interaction with intercellular adhesion molecule-1 (ICAM-1) on inflamed endothelial cells. After entering IMEs, the HA coating would be degraded and detached to expose the cationic surface of the Omi-hyd-Dex core and enable it to accumulate in IMEs. Meanwhile, the hydrazone bond between omiganan and Dex could be cleaved in response to the acidic condition of IMEs, thereby releasing the cationic peptide and anti-inflammatory agent that would concurrently inhibit the infection and inflammation precisely."
REF00291	PDC_00254	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	32 &micro;g/mL	&micro;g/mL	.	.	.	.	Candida albicans infection	Candida albicans fungus strains	.	.	18 h	.	MIC assay	"To verify whether Omi-hyd-Dex@HA NPs inherited the antimicrobial activity of omiganan, the MICs were tested by the standardized agar doubling-dilution method as shown in Table 1. Omi-hyd-Dex@HA NPs and free omiganan showed similar extended broad-spectrum antibacterial activity for G+ bacteria, G- bacteria and fungi pathogens, including drug-sensitive strains (S. aureus, P. aeruginosa, K.P., Candida albicans) and drug-resistant strains (MRSA, MDR-K.P.). The MICs of Omi-hyd-Dex@HA NPs showed none or only a one-fold increase compared with the free Omiganan-NHNH2 group. In addition, free Dex did not show any antimicrobial activity for the tested pathogens, indicating that Dex moieties of Omi-hyd-Dex@HA NPs did not contribute to the bacterial killing effect. In contrast, vancomycin, as a standard drug regimen for drug-resistant G+ strains, showed inefficacious for G- strains and fungus. Similar results were also observed in oxacillin-treated groups. Therefore, Omi-hyd-Dex@HA NPs retained the broad-spectrum antimicrobial activity of omiganan."	"To minimize the toxic side effect of omiganan and optimize its anti-inflammatory capability, we designed an IMEs-responsive self-delivery nanosystem consisting of omiganan, an anti-inflammatory agent, and natural polysaccharide to achieve on-demand degradation and responsive drug release. Based on the cationic hydrophilic fragments on omiganan, we chose dexamethasone (Dex, a hydrophobic anti-inflammatory drug) to link with this peptide via a hydrazone bond to construct an amphiphilic conjugate (Omi-hyd-Dex). With the assistance of PLGA, this conjugate could self-assemble into nanoparticles (Omi-hyd-Dex NPs) in an aqueous solution without introducing any other hazardous materials. Then, the negatively-charged hyaluronic acid (HA, a natural ligand of ICAM-1 and CD44) was used to coat Omi-hyd-Dex NPs to form a core-shell structural formulation (Omi-hyd-Dex@HA NPs). This HA coating could not only eliminate the hemolytic activity of omiganan to reduce side effects but also act as the IMEs targeting molecule through interaction with intercellular adhesion molecule-1 (ICAM-1) on inflamed endothelial cells. After entering IMEs, the HA coating would be degraded and detached to expose the cationic surface of the Omi-hyd-Dex core and enable it to accumulate in IMEs. Meanwhile, the hydrazone bond between omiganan and Dex could be cleaved in response to the acidic condition of IMEs, thereby releasing the cationic peptide and anti-inflammatory agent that would concurrently inhibit the infection and inflammation precisely."
REF00290	PDC_00065	DOX-induced cardiomyopathy	.	Revealed Based on the Cell Line Data	.	MDA increase rate	50%	%	.	.	.	.	Normal	H9c2 cell	.	.	24 h	100 &micro;M	Western blotting assay	"The accumulation of iron is a characteristic feature of ferroptosis. Intracellular iron, especially labile ferrous iron, can react with oxidants to generate cytotoxic hydroxyl radicals via Fenton reactions, thereby promoting ferroptosis. FerroOrange staining revealed significantly increased intracellular Fe2+ levels in DOX-treated H9c2 cells compared to controls, indicating DOX induced iron dyshomeostasis, resulting in ferrous iron buildup and subsequent ferroptosis. BA-NFs alleviated the accumulation of intracellular ferrous ions, suppressing ferroptosis. Fe2+ accumulation may disrupt the balance between LPO and oxygen homeostasis. We observed that BA-NFs efficiently attenuated DOX-induced elevation in malondialdehyde (MDA), a lipid peroxidation end-product, while increased antioxidant glutathione (GSH) levels. These findings suggested that BA-NFs can prevent DOX-induced ferroptosis in cardiomyocytes. Furthermore, protein expression of SLC7A11 and GPX4, key components of the antioxidant defense system against ferroptosis, was examined. DOX significantly decreased SLC7A11 and GPX4 expression in H9c2 cells compared to controls, suggesting DOX disrupts cellular antioxidant systems leading to ferroptosis. BA and BA-NFs partially restored SLC7A11 and GPX4 expression versus DOX treatment, with BA-NFs exhibiting the most significant impact. Together, these results indicate BA-NFs specifically inhibits DOX-induced cardiomyocyte ferroptosis by reducing intracellular iron accumulation and enhancing antioxidant system gene expression. In addition, the cardiotoxic effects of DOX are mediated via excessive oxidative stress and induced mitochondrial damage, thereby activating intrinsic apoptosis as an additional pathway. Flow cytometric analysis using Annexin V-Fitc/PI staining revealed that BA-NFs potently attenuated DOX-induced cardiomyocyte apoptosis, with a more pronounced effect than BA alone. DOX enhanced the green fluorescent signal of cleaved caspase-3 (as a biomarker of apoptosis) in H9c2 cells, whereas BA-NFs significantly inhibited this upregulation. These results provided further evidence that BA-NFs serve as potential therapeutic approaches for DIC."	"Based on the above background, we designed and synthesized supramolecular self-assembled nanofibers with AT1R-specific targeting moieties (Baicalin-FFYEEG-ARVYIHPF, BA-NFs). Baicalin (BA), with its capacity for ROS scavenging and ferroptosis inhibition, constitutes an ideal candidate for ameliorating DIC. BA was conjugated with the self-assembling peptide FF and targeting peptide ARVYIHPF to form a specific nanostructure to improve its aqueous solubility and incorporate a targeting functionality, thereby addressing its inherent limitations. Our results indicated BA-NFs can mitigate doxorubicin-induced cardiomyocyte ferroptosis and cardiac dysfunction. This remarkable therapeutic effect is primarily attributable to the targeting proficiency of BA-NFs for injured cardiomyocytes, culminating in superoxide and ROS scavenging, reduced iron deposition, alleviated lipid peroxidation, and enhanced SLC7A11 and GPX4 expression. Therefore, we propose that BA-NFs proffers an efficacious targeted drug delivery strategy for the amelioration of DIC."
REF00290	PDC_00065	DOX-induced cardiomyopathy	.	Revealed Based on the Cell Line Data	.	GSH/GSSG increase ratio	85%	%	.	.	.	.	Normal	H9c2 cell	.	.	24 h	100 &micro;M	Western blotting assay	"The accumulation of iron is a characteristic feature of ferroptosis. Intracellular iron, especially labile ferrous iron, can react with oxidants to generate cytotoxic hydroxyl radicals via Fenton reactions, thereby promoting ferroptosis. FerroOrange staining revealed significantly increased intracellular Fe2+ levels in DOX-treated H9c2 cells compared to controls, indicating DOX induced iron dyshomeostasis, resulting in ferrous iron buildup and subsequent ferroptosis. BA-NFs alleviated the accumulation of intracellular ferrous ions, suppressing ferroptosis. Fe2+ accumulation may disrupt the balance between LPO and oxygen homeostasis. We observed that BA-NFs efficiently attenuated DOX-induced elevation in malondialdehyde (MDA), a lipid peroxidation end-product, while increased antioxidant glutathione (GSH) levels. These findings suggested that BA-NFs can prevent DOX-induced ferroptosis in cardiomyocytes. Furthermore, protein expression of SLC7A11 and GPX4, key components of the antioxidant defense system against ferroptosis, was examined. DOX significantly decreased SLC7A11 and GPX4 expression in H9c2 cells compared to controls, suggesting DOX disrupts cellular antioxidant systems leading to ferroptosis. BA and BA-NFs partially restored SLC7A11 and GPX4 expression versus DOX treatment, with BA-NFs exhibiting the most significant impact. Together, these results indicate BA-NFs specifically inhibits DOX-induced cardiomyocyte ferroptosis by reducing intracellular iron accumulation and enhancing antioxidant system gene expression. In addition, the cardiotoxic effects of DOX are mediated via excessive oxidative stress and induced mitochondrial damage, thereby activating intrinsic apoptosis as an additional pathway. Flow cytometric analysis using Annexin V-Fitc/PI staining revealed that BA-NFs potently attenuated DOX-induced cardiomyocyte apoptosis, with a more pronounced effect than BA alone. DOX enhanced the green fluorescent signal of cleaved caspase-3 (as a biomarker of apoptosis) in H9c2 cells, whereas BA-NFs significantly inhibited this upregulation. These results provided further evidence that BA-NFs serve as potential therapeutic approaches for DIC."	"Based on the above background, we designed and synthesized supramolecular self-assembled nanofibers with AT1R-specific targeting moieties (Baicalin-FFYEEG-ARVYIHPF, BA-NFs). Baicalin (BA), with its capacity for ROS scavenging and ferroptosis inhibition, constitutes an ideal candidate for ameliorating DIC. BA was conjugated with the self-assembling peptide FF and targeting peptide ARVYIHPF to form a specific nanostructure to improve its aqueous solubility and incorporate a targeting functionality, thereby addressing its inherent limitations. Our results indicated BA-NFs can mitigate doxorubicin-induced cardiomyocyte ferroptosis and cardiac dysfunction. This remarkable therapeutic effect is primarily attributable to the targeting proficiency of BA-NFs for injured cardiomyocytes, culminating in superoxide and ROS scavenging, reduced iron deposition, alleviated lipid peroxidation, and enhanced SLC7A11 and GPX4 expression. Therefore, we propose that BA-NFs proffers an efficacious targeted drug delivery strategy for the amelioration of DIC."
REF00290	PDC_00065	DOX-induced cardiomyopathy	.	Revealed Based on the Cell Line Data	.	Fe2+ decrease ratio	50%	%	.	.	.	.	Normal	H9c2 cell	.	.	24 h	100 &micro;M	Western blotting assay	"The accumulation of iron is a characteristic feature of ferroptosis. Intracellular iron, especially labile ferrous iron, can react with oxidants to generate cytotoxic hydroxyl radicals via Fenton reactions, thereby promoting ferroptosis. FerroOrange staining revealed significantly increased intracellular Fe2+ levels in DOX-treated H9c2 cells compared to controls, indicating DOX induced iron dyshomeostasis, resulting in ferrous iron buildup and subsequent ferroptosis. BA-NFs alleviated the accumulation of intracellular ferrous ions, suppressing ferroptosis. Fe2+ accumulation may disrupt the balance between LPO and oxygen homeostasis. We observed that BA-NFs efficiently attenuated DOX-induced elevation in malondialdehyde (MDA), a lipid peroxidation end-product, while increased antioxidant glutathione (GSH) levels. These findings suggested that BA-NFs can prevent DOX-induced ferroptosis in cardiomyocytes. Furthermore, protein expression of SLC7A11 and GPX4, key components of the antioxidant defense system against ferroptosis, was examined. DOX significantly decreased SLC7A11 and GPX4 expression in H9c2 cells compared to controls, suggesting DOX disrupts cellular antioxidant systems leading to ferroptosis. BA and BA-NFs partially restored SLC7A11 and GPX4 expression versus DOX treatment, with BA-NFs exhibiting the most significant impact. Together, these results indicate BA-NFs specifically inhibits DOX-induced cardiomyocyte ferroptosis by reducing intracellular iron accumulation and enhancing antioxidant system gene expression. In addition, the cardiotoxic effects of DOX are mediated via excessive oxidative stress and induced mitochondrial damage, thereby activating intrinsic apoptosis as an additional pathway. Flow cytometric analysis using Annexin V-Fitc/PI staining revealed that BA-NFs potently attenuated DOX-induced cardiomyocyte apoptosis, with a more pronounced effect than BA alone. DOX enhanced the green fluorescent signal of cleaved caspase-3 (as a biomarker of apoptosis) in H9c2 cells, whereas BA-NFs significantly inhibited this upregulation. These results provided further evidence that BA-NFs serve as potential therapeutic approaches for DIC."	"Based on the above background, we designed and synthesized supramolecular self-assembled nanofibers with AT1R-specific targeting moieties (Baicalin-FFYEEG-ARVYIHPF, BA-NFs). Baicalin (BA), with its capacity for ROS scavenging and ferroptosis inhibition, constitutes an ideal candidate for ameliorating DIC. BA was conjugated with the self-assembling peptide FF and targeting peptide ARVYIHPF to form a specific nanostructure to improve its aqueous solubility and incorporate a targeting functionality, thereby addressing its inherent limitations. Our results indicated BA-NFs can mitigate doxorubicin-induced cardiomyocyte ferroptosis and cardiac dysfunction. This remarkable therapeutic effect is primarily attributable to the targeting proficiency of BA-NFs for injured cardiomyocytes, culminating in superoxide and ROS scavenging, reduced iron deposition, alleviated lipid peroxidation, and enhanced SLC7A11 and GPX4 expression. Therefore, we propose that BA-NFs proffers an efficacious targeted drug delivery strategy for the amelioration of DIC."
REF00290	PDC_00065	DOX-induced cardiomyopathy	.	Revealed Based on the Cell Line Data	.	GPX4/GAPDH increase ratio	120%	%	.	.	.	.	Normal	H9c2 cell	.	.	24 h	100 &micro;M	Western blotting assay	"The accumulation of iron is a characteristic feature of ferroptosis. Intracellular iron, especially labile ferrous iron, can react with oxidants to generate cytotoxic hydroxyl radicals via Fenton reactions, thereby promoting ferroptosis. FerroOrange staining revealed significantly increased intracellular Fe2+ levels in DOX-treated H9c2 cells compared to controls, indicating DOX induced iron dyshomeostasis, resulting in ferrous iron buildup and subsequent ferroptosis. BA-NFs alleviated the accumulation of intracellular ferrous ions, suppressing ferroptosis. Fe2+ accumulation may disrupt the balance between LPO and oxygen homeostasis. We observed that BA-NFs efficiently attenuated DOX-induced elevation in malondialdehyde (MDA), a lipid peroxidation end-product, while increased antioxidant glutathione (GSH) levels. These findings suggested that BA-NFs can prevent DOX-induced ferroptosis in cardiomyocytes. Furthermore, protein expression of SLC7A11 and GPX4, key components of the antioxidant defense system against ferroptosis, was examined. DOX significantly decreased SLC7A11 and GPX4 expression in H9c2 cells compared to controls, suggesting DOX disrupts cellular antioxidant systems leading to ferroptosis. BA and BA-NFs partially restored SLC7A11 and GPX4 expression versus DOX treatment, with BA-NFs exhibiting the most significant impact. Together, these results indicate BA-NFs specifically inhibits DOX-induced cardiomyocyte ferroptosis by reducing intracellular iron accumulation and enhancing antioxidant system gene expression. In addition, the cardiotoxic effects of DOX are mediated via excessive oxidative stress and induced mitochondrial damage, thereby activating intrinsic apoptosis as an additional pathway. Flow cytometric analysis using Annexin V-Fitc/PI staining revealed that BA-NFs potently attenuated DOX-induced cardiomyocyte apoptosis, with a more pronounced effect than BA alone. DOX enhanced the green fluorescent signal of cleaved caspase-3 (as a biomarker of apoptosis) in H9c2 cells, whereas BA-NFs significantly inhibited this upregulation. These results provided further evidence that BA-NFs serve as potential therapeutic approaches for DIC."	"Based on the above background, we designed and synthesized supramolecular self-assembled nanofibers with AT1R-specific targeting moieties (Baicalin-FFYEEG-ARVYIHPF, BA-NFs). Baicalin (BA), with its capacity for ROS scavenging and ferroptosis inhibition, constitutes an ideal candidate for ameliorating DIC. BA was conjugated with the self-assembling peptide FF and targeting peptide ARVYIHPF to form a specific nanostructure to improve its aqueous solubility and incorporate a targeting functionality, thereby addressing its inherent limitations. Our results indicated BA-NFs can mitigate doxorubicin-induced cardiomyocyte ferroptosis and cardiac dysfunction. This remarkable therapeutic effect is primarily attributable to the targeting proficiency of BA-NFs for injured cardiomyocytes, culminating in superoxide and ROS scavenging, reduced iron deposition, alleviated lipid peroxidation, and enhanced SLC7A11 and GPX4 expression. Therefore, we propose that BA-NFs proffers an efficacious targeted drug delivery strategy for the amelioration of DIC."
REF00290	PDC_00065	DOX-induced cardiomyopathy	.	Revealed Based on the Cell Line Data	.	SLC7A11/GAPDH increase rate	83%	%	.	.	.	.	Normal	H9c2 cell	.	.	24 h	100 &micro;M	Western blotting assay	"The accumulation of iron is a characteristic feature of ferroptosis. Intracellular iron, especially labile ferrous iron, can react with oxidants to generate cytotoxic hydroxyl radicals via Fenton reactions, thereby promoting ferroptosis. FerroOrange staining revealed significantly increased intracellular Fe2+ levels in DOX-treated H9c2 cells compared to controls, indicating DOX induced iron dyshomeostasis, resulting in ferrous iron buildup and subsequent ferroptosis. BA-NFs alleviated the accumulation of intracellular ferrous ions, suppressing ferroptosis. Fe2+ accumulation may disrupt the balance between LPO and oxygen homeostasis. We observed that BA-NFs efficiently attenuated DOX-induced elevation in malondialdehyde (MDA), a lipid peroxidation end-product, while increased antioxidant glutathione (GSH) levels. These findings suggested that BA-NFs can prevent DOX-induced ferroptosis in cardiomyocytes. Furthermore, protein expression of SLC7A11 and GPX4, key components of the antioxidant defense system against ferroptosis, was examined. DOX significantly decreased SLC7A11 and GPX4 expression in H9c2 cells compared to controls, suggesting DOX disrupts cellular antioxidant systems leading to ferroptosis. BA and BA-NFs partially restored SLC7A11 and GPX4 expression versus DOX treatment, with BA-NFs exhibiting the most significant impact. Together, these results indicate BA-NFs specifically inhibits DOX-induced cardiomyocyte ferroptosis by reducing intracellular iron accumulation and enhancing antioxidant system gene expression. In addition, the cardiotoxic effects of DOX are mediated via excessive oxidative stress and induced mitochondrial damage, thereby activating intrinsic apoptosis as an additional pathway. Flow cytometric analysis using Annexin V-Fitc/PI staining revealed that BA-NFs potently attenuated DOX-induced cardiomyocyte apoptosis, with a more pronounced effect than BA alone. DOX enhanced the green fluorescent signal of cleaved caspase-3 (as a biomarker of apoptosis) in H9c2 cells, whereas BA-NFs significantly inhibited this upregulation. These results provided further evidence that BA-NFs serve as potential therapeutic approaches for DIC."	"Based on the above background, we designed and synthesized supramolecular self-assembled nanofibers with AT1R-specific targeting moieties (Baicalin-FFYEEG-ARVYIHPF, BA-NFs). Baicalin (BA), with its capacity for ROS scavenging and ferroptosis inhibition, constitutes an ideal candidate for ameliorating DIC. BA was conjugated with the self-assembling peptide FF and targeting peptide ARVYIHPF to form a specific nanostructure to improve its aqueous solubility and incorporate a targeting functionality, thereby addressing its inherent limitations. Our results indicated BA-NFs can mitigate doxorubicin-induced cardiomyocyte ferroptosis and cardiac dysfunction. This remarkable therapeutic effect is primarily attributable to the targeting proficiency of BA-NFs for injured cardiomyocytes, culminating in superoxide and ROS scavenging, reduced iron deposition, alleviated lipid peroxidation, and enhanced SLC7A11 and GPX4 expression. Therefore, we propose that BA-NFs proffers an efficacious targeted drug delivery strategy for the amelioration of DIC."
REF00289	PDC_00175	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	200 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	GPC3 positive HepG2 cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00175	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.7 &plusmn; 0.19 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	GPC3 positive HepG2 cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00175	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	200 &micro;M	&micro;M	.	.	.	.	Adult hepatocellular carcinoma	GPC3-positive Huh-7 cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00175	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.9 &plusmn; 0.44 &micro;M	&micro;M	.	.	.	.	Adult hepatocellular carcinoma	GPC3-positive Huh-7 cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00175	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	200 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	GPC3 negative MCF7 cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00175	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.3 &plusmn; 1.0 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	GPC3 negative MCF7 cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00175	Cervical cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	200 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	GPC3-negative HeLa cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00175	Cervical cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.7 &plusmn; 1.1 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	GPC3-negative HeLa cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00175	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	200 &micro;M	&micro;M	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00175	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.8 &plusmn; 1.0 &micro;M	&micro;M	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00176	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	GPC3 positive HepG2 cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00176	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.82 &plusmn; 0.06 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	GPC3 positive HepG2 cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00176	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Adult hepatocellular carcinoma	GPC3-positive Huh-7 cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00176	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.4 &plusmn; 0.60 &micro;M	&micro;M	.	.	.	.	Adult hepatocellular carcinoma	GPC3-positive Huh-7 cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00176	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	GPC3 negative MCF7 cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00176	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	GPC3 negative MCF7 cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00176	Cervical cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	GPC3-negative HeLa cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00176	Cervical cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	GPC3-negative HeLa cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00176	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	200 &micro;M	&micro;M	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00176	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10 &micro;M	&micro;M	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00177	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	GPC3 positive HepG2 cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00177	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.31 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	GPC3 positive HepG2 cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00177	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Adult hepatocellular carcinoma	GPC3-positive Huh-7 cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00177	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.25 &plusmn; 0.03 &micro;M	&micro;M	.	.	.	.	Adult hepatocellular carcinoma	GPC3-positive Huh-7 cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00177	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	GPC3 negative MCF7 cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00177	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.88 &plusmn; 0.07 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	GPC3 negative MCF7 cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00177	Cervical cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	GPC3-negative HeLa cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00177	Cervical cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.72 &plusmn; 0.12 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	GPC3-negative HeLa cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00177	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	200 &micro;M	&micro;M	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00177	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.1 &plusmn; 0.9 &micro;M	&micro;M	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00178	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	200 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	GPC3 positive HepG2 cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00178	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.33 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	GPC3 positive HepG2 cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00178	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	200 &micro;M	&micro;M	.	.	.	.	Adult hepatocellular carcinoma	GPC3-positive Huh-7 cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00178	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.34 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Adult hepatocellular carcinoma	GPC3-positive Huh-7 cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00178	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	200 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	GPC3 negative MCF7 cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00178	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.79 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	GPC3 negative MCF7 cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00178	Cervical cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	200 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	GPC3-negative HeLa cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00178	Cervical cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.57 &plusmn; 0.05 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	GPC3-negative HeLa cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00178	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	200 &micro;M	&micro;M	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	Dark toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00289	PDC_00178	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.38 &plusmn; 0.03 &micro;M	&micro;M	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	Light toxicity	24 h	.	Annexin V/PI staining assay	"Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm<sup>2</sup>), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM)."	"Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC."
REF00288	PDC_00331	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.85 &plusmn; 0.23 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00332	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.59 &plusmn; 0.40 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00333	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	18.34 &plusmn; 1.42 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00334	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.53 &plusmn; 0.17 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00335	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.78 &plusmn; 0.35 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00336	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.68 &plusmn; 1.14 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00337	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.58 &plusmn; 0.21 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00338	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.30 &plusmn; 0.48 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00339	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	12.58 &plusmn; 2.45 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00331	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.04 &plusmn; 0.75 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00332	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.93 &plusmn; 0.46 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00333	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	25.31 &plusmn; 1.48 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00334	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.58 &plusmn; 0.41 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00335	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.53 &plusmn; 1.02 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00336	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	20.14 &plusmn; 2.12 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00337	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.86 &plusmn; 1.84 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00338	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.01 &plusmn; 1.34 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00339	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	24.15 &plusmn; 3.76 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00331	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.03 &plusmn; 0.25 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00332	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.24 &plusmn; 0.57 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00333	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00334	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.50 &plusmn; 0.78 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00335	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.81 &plusmn; 1.08 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00336	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00337	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.17 &plusmn; 1.21 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00338	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.73 &plusmn; 1.33 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00339	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00331	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.43 &plusmn; 1.20 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00332	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.64 &plusmn; 1.32 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00333	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	30.58 &plusmn; 2.76 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00334	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	18.44 &plusmn; 2.09 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00335	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	16.24 &plusmn; 1.04 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00336	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	28.21 &plusmn; 1.28 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00337	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.73 &plusmn; 1.55 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00338	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.11 &plusmn; 1.80 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00339	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	31.35 &plusmn; 3.17 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00331	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	18.23 &plusmn; 2.06 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00332	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.13 &plusmn; 1.24 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00333	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00334	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	17.76 &plusmn; 1.35 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00335	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	22.12 &plusmn; 1.83 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00336	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00337	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.15 &plusmn; 1.44 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00338	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	28.36 &plusmn; 2.12 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00288	PDC_00339	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	CCK-8 assay	"HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, and HER2 negative MDA-MB-231 and MCF-10A cells were selected to determine the cell activity of the target conjugates. From Table 3, most conjugates showed certain cytotoxicity to three HER2 positive cell lines. Among the three connection sites (S1-S3), compounds 1, 4, and 7 with the first connection mode showed better activity. In the three HER2 positive SK-BR-3, NCI-N87 and SK-OV-3 cells, conjugate 4 exhibited superior activity (IC50s of 0.53 &plusmn; 0.17 uM, 1.58 &plusmn; 0.41 uM, 2.50 &plusmn; 0.78 uM, respectively), which almost equal to that of CPT (IC50s of 0.38 &plusmn; 0.11 uM, 2.07 &plusmn; 0.67 uM, 4.07 &plusmn; 1.82 uM, respectively). The activity of conjugate 4 on HER2 positive cells was superior to that of conjugate 1 and 7. In MDA-MB-231 and MCF-10A cells, IC50s of conjugate 4 were 18.44 &plusmn; 2.09 uM and 17.76 &plusmn; 1.35 uM, respectively, which showed great tumor cell selectivity. Based on the above, conjugate 4 with better in vitro antitumor activity was selected for subsequent biological study."	"In this study, a series of conjugates were designed and synthesized by fusing the SMAC peptide and P1 target peptide, and coupling with CPT, with the hope that they can play a synergistic role in promoting cell apoptosis. The in vitro anti-tumor activity study found that the better conjugate 4 had the best activity on HER2-positive cells, while it was less toxic to HER2-negative cells. From the experimental results, the coupling position of CPT affected the activity of the conjugates. Conjugates 1, 4 and 7, which connected the load in the same way, had different inhibitory activities on three HER2-positive cells, and among them, conjugate 4 showed the best activity. We speculated it is related to the releasing efficiency of free SMAC peptide and CPT. The subsequent biological activity evaluations of conjugate 4 confirmed that the introduction of the SMAC peptide sequence can enhance the activity of Caspase 3 and indeed play a role in promoting apoptosis. Conjugate 4 reduced the expression of XIAP and cIAP1 in SK-BR-3 cells in a concentration dependent manner. The in vivo activity study also fully proved that the antitumor activity as well as safety of conjugate 4 was superior to CPT. The pro-apoptotic effect of conjugate 4 is significantly superior to the C4 group without fused SMAC peptide and the C4+SMAC combination drug group. This indicates that that the introduced SMAC peptide exerts a synergistic anti-tumor effect. When CPT is engineered into PDCs molecules, its in vitro activity related to CPT can be retained but is somewhat diminished. This attenuation may be attributed to the fact that PDCs must undergo cellular internalization and release of CPT or its derivatives in the intracellular environment to exert anti-tumor activity."
REF00287	PDC_00125	Pain	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	2.0 &plusmn; 0.1 x 10<sup>-9</sup> mol	nM	.	.	.	.	Normal	HEK-293T cell	.	.	.	.	Potency/efficacy cAMP assay)	"We obtained four DNCP--NalA conjugates (1-4); the conjugation of DNCP (35) and DNCP (36) was unsuccessful. DNCP--NalA conjugates (1-4) were pharmacologically characterized via radioligand binding and functional cAMP assays to investigate their affinity, potency and efficacy at the mouse KOR. The DNCP--NalA conjugates exhibited affinities in the low nanomolar range, with DNCP--NalA(1) being the strongest binder at KOR with a Ki value of 3.9 nM, as compared to -NalA, which has an affinity Ki of 72 nM. All four DNCP--NalA conjugates were full agonists at KOR (Emax = 89-101%), while -NalA alone was only a partial agonist with an EC50 of 130 nM and Emax of 61%. The most potent conjugates were DNCP--NalA(1) and (4) with EC50 values of 2.0 nM and 1.0 nM, respectively. DNCP--NalA(2) and DNCP--NalA(3) showed agonist activities at KOR with EC50 values of 7.5 and 14 nM in cAMP assay, respectively, while their Ki values were 31 and 24 nM in radioligand binding assay, respectively. Receptor reserve may account for this discrepancy between potency and affinity values of DNCP--NalA(2) and DNCP--NalA(4) which can be observed in functional GPCR assays with opioid receptors30. The higher potency and efficacy of the conjugates at KOR compared to -NalA can be attributed to interactions of the macrocycles with the ECL2 region as described later."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00126	Pain	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	7.5 &plusmn; 0.6 x 10<sup>-9</sup> mol	nM	.	.	.	.	Normal	HEK-293T cell	.	.	.	.	Potency/efficacy cAMP assay	"We obtained four DNCP--NalA conjugates (1-4); the conjugation of DNCP (35) and DNCP (36) was unsuccessful. DNCP--NalA conjugates (1-4) were pharmacologically characterized via radioligand binding and functional cAMP assays to investigate their affinity, potency and efficacy at the mouse KOR. The DNCP--NalA conjugates exhibited affinities in the low nanomolar range, with DNCP--NalA(1) being the strongest binder at KOR with a Ki value of 3.9 nM, as compared to -NalA, which has an affinity Ki of 72 nM. All four DNCP--NalA conjugates were full agonists at KOR (Emax = 89-101%), while -NalA alone was only a partial agonist with an EC50 of 130 nM and Emax of 61%. The most potent conjugates were DNCP--NalA(1) and (4) with EC50 values of 2.0 nM and 1.0 nM, respectively. DNCP--NalA(2) and DNCP--NalA(3) showed agonist activities at KOR with EC50 values of 7.5 and 14 nM in cAMP assay, respectively, while their Ki values were 31 and 24 nM in radioligand binding assay, respectively. Receptor reserve may account for this discrepancy between potency and affinity values of DNCP--NalA(2) and DNCP--NalA(4) which can be observed in functional GPCR assays with opioid receptors30. The higher potency and efficacy of the conjugates at KOR compared to -NalA can be attributed to interactions of the macrocycles with the ECL2 region as described later."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00127	Pain	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	1.4 &plusmn; 0.7 x 10<sup>-8</sup> mol	nM	.	.	.	.	Normal	HEK-293T cell	.	.	.	.	Potency/efficacy cAMP assay	"We obtained four DNCP--NalA conjugates (1-4); the conjugation of DNCP (35) and DNCP (36) was unsuccessful. DNCP--NalA conjugates (1-4) were pharmacologically characterized via radioligand binding and functional cAMP assays to investigate their affinity, potency and efficacy at the mouse KOR. The DNCP--NalA conjugates exhibited affinities in the low nanomolar range, with DNCP--NalA(1) being the strongest binder at KOR with a Ki value of 3.9 nM, as compared to -NalA, which has an affinity Ki of 72 nM. All four DNCP--NalA conjugates were full agonists at KOR (Emax = 89-101%), while -NalA alone was only a partial agonist with an EC50 of 130 nM and Emax of 61%. The most potent conjugates were DNCP--NalA(1) and (4) with EC50 values of 2.0 nM and 1.0 nM, respectively. DNCP--NalA(2) and DNCP--NalA(3) showed agonist activities at KOR with EC50 values of 7.5 and 14 nM in cAMP assay, respectively, while their Ki values were 31 and 24 nM in radioligand binding assay, respectively. Receptor reserve may account for this discrepancy between potency and affinity values of DNCP--NalA(2) and DNCP--NalA(4) which can be observed in functional GPCR assays with opioid receptors30. The higher potency and efficacy of the conjugates at KOR compared to -NalA can be attributed to interactions of the macrocycles with the ECL2 region as described later."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00128	Pain	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	1.0 &plusmn; 0.1 x 10<sup>-9</sup> mol	nM	.	.	.	.	Normal	HEK-293T cell	.	.	.	.	Potency/efficacy cAMP assay	"We obtained four DNCP--NalA conjugates (1-4); the conjugation of DNCP (35) and DNCP (36) was unsuccessful. DNCP--NalA conjugates (1-4) were pharmacologically characterized via radioligand binding and functional cAMP assays to investigate their affinity, potency and efficacy at the mouse KOR. The DNCP--NalA conjugates exhibited affinities in the low nanomolar range, with DNCP--NalA(1) being the strongest binder at KOR with a Ki value of 3.9 nM, as compared to -NalA, which has an affinity Ki of 72 nM. All four DNCP--NalA conjugates were full agonists at KOR (Emax = 89-101%), while -NalA alone was only a partial agonist with an EC50 of 130 nM and Emax of 61%. The most potent conjugates were DNCP--NalA(1) and (4) with EC50 values of 2.0 nM and 1.0 nM, respectively. DNCP--NalA(2) and DNCP--NalA(3) showed agonist activities at KOR with EC50 values of 7.5 and 14 nM in cAMP assay, respectively, while their Ki values were 31 and 24 nM in radioligand binding assay, respectively. Receptor reserve may account for this discrepancy between potency and affinity values of DNCP--NalA(2) and DNCP--NalA(4) which can be observed in functional GPCR assays with opioid receptors30. The higher potency and efficacy of the conjugates at KOR compared to -NalA can be attributed to interactions of the macrocycles with the ECL2 region as described later."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00125	Pain	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	2.2 &plusmn; 1.3 x 10<sup>-8</sup> mol	nM	.	.	.	.	Normal	HEK-293T cell	.	.	.	.	Potency/efficacy &beta;-arrestin-2 recruitment assay	"We obtained four DNCP--NalA conjugates (1-4); the conjugation of DNCP (35) and DNCP (36) was unsuccessful. DNCP--NalA conjugates (1-4) were pharmacologically characterized via radioligand binding and functional cAMP assays to investigate their affinity, potency and efficacy at the mouse KOR. The DNCP--NalA conjugates exhibited affinities in the low nanomolar range, with DNCP--NalA(1) being the strongest binder at KOR with a Ki value of 3.9 nM, as compared to -NalA, which has an affinity Ki of 72 nM. All four DNCP--NalA conjugates were full agonists at KOR (Emax = 89-101%), while -NalA alone was only a partial agonist with an EC50 of 130 nM and Emax of 61%. The most potent conjugates were DNCP--NalA(1) and (4) with EC50 values of 2.0 nM and 1.0 nM, respectively. DNCP--NalA(2) and DNCP--NalA(3) showed agonist activities at KOR with EC50 values of 7.5 and 14 nM in cAMP assay, respectively, while their Ki values were 31 and 24 nM in radioligand binding assay, respectively. Receptor reserve may account for this discrepancy between potency and affinity values of DNCP--NalA(2) and DNCP--NalA(4) which can be observed in functional GPCR assays with opioid receptors30. The higher potency and efficacy of the conjugates at KOR compared to -NalA can be attributed to interactions of the macrocycles with the ECL2 region as described later."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00125	Pain	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	2.8 &plusmn; 0.7 x 10<sup>-8</sup> mol	nM	.	.	.	.	Normal	HEK-293T cell	.	.	.	.	Potency/efficacy &beta;-arrestin-1 recruitment assay	"We obtained four DNCP--NalA conjugates (1-4); the conjugation of DNCP (35) and DNCP (36) was unsuccessful. DNCP--NalA conjugates (1-4) were pharmacologically characterized via radioligand binding and functional cAMP assays to investigate their affinity, potency and efficacy at the mouse KOR. The DNCP--NalA conjugates exhibited affinities in the low nanomolar range, with DNCP--NalA(1) being the strongest binder at KOR with a Ki value of 3.9 nM, as compared to -NalA, which has an affinity Ki of 72 nM. All four DNCP--NalA conjugates were full agonists at KOR (Emax = 89-101%), while -NalA alone was only a partial agonist with an EC50 of 130 nM and Emax of 61%. The most potent conjugates were DNCP--NalA(1) and (4) with EC50 values of 2.0 nM and 1.0 nM, respectively. DNCP--NalA(2) and DNCP--NalA(3) showed agonist activities at KOR with EC50 values of 7.5 and 14 nM in cAMP assay, respectively, while their Ki values were 31 and 24 nM in radioligand binding assay, respectively. Receptor reserve may account for this discrepancy between potency and affinity values of DNCP--NalA(2) and DNCP--NalA(4) which can be observed in functional GPCR assays with opioid receptors30. The higher potency and efficacy of the conjugates at KOR compared to -NalA can be attributed to interactions of the macrocycles with the ECL2 region as described later."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00125	Pain	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	5.5 &plusmn; 1.7 x 10<sup>-9</sup> mol	nM	.	.	.	.	Normal	CHO cell	.	.	.	.	[<sup>35</sup>S]GTP&gamma;S binding assay	"Next, we determined the opioid receptor subtype selectivity profile of DNCP--NalA(1) in radioligand binding assays with membrane preparations from HEK293 cells stably expressing the mouse MOR and DOR, and CHO cells stably expressing human nociceptin (NOP) receptor. Herein, DNCP--NalA(1) bound to mouse MOR and DOR with Ki values of 5.4 and 318 nM, respectively, supporting an ~80-fold selectivity for KOR over DOR whereas it bound to the human NOP with a Ki value of ~1.3 &mu;M, thus having an ~330-fold selectivity for KOR over NOP receptor. In the functional cAMP assay, DNCP--NalA(1) was inactive at both mouse MOR and DOR up to 10 &mu;M. This was confirmed at the human MOR and DOR in the [<sup>35</sup>S]GTP&gamma;S binding assay. We next determined the mechanism of antagonism of DNCP--NalA(1) by measuring adenylyl cyclase-mediated cAMP inhibition and [<sup>35</sup>S]GTP&gamma;S binding at mouse and human MOR, respectively, using Schild regression analysis. The MOR expressed in HEK293 and CHO cells was activated by DAMGO in the absence and presence of increasing concentrations of DNCP--NalA(1). We observed a rightward shift of the concentration-response curves of DAMGO in cAMP and [<sup>35</sup>S]GTP&gamma;S binding assays. Schild analysis of DNCP--NalA(1) exhibited linear regression slopes of 0.9 and 1.5 and pA2 values of 9.1 and 7.9 in cAMP and [<sup>35</sup>S]GTP&gamma;S binding assays, respectively, which corresponds to an average functional affinity of 0.8 and 13 nM, respectively, thus demonstrating the competitive antagonism of the DNCP--NalA(1) at MOR."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00125	Pain	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	31 &plusmn; 15 &mu;M	&mu;M	.	.	.	.	Normal	CHO cell	.	.	.	.	[<sup>35</sup>S]GTP&gamma;S binding assay	"Next, we determined the opioid receptor subtype selectivity profile of DNCP--NalA(1) in radioligand binding assays with membrane preparations from HEK293 cells stably expressing the mouse MOR and DOR, and CHO cells stably expressing human nociceptin (NOP) receptor. Herein, DNCP--NalA(1) bound to mouse MOR and DOR with Ki values of 5.4 and 318 nM, respectively, supporting an ~80-fold selectivity for KOR over DOR whereas it bound to the human NOP with a Ki value of ~1.3 &mu;M, thus having an ~330-fold selectivity for KOR over NOP receptor. In the functional cAMP assay, DNCP--NalA(1) was inactive at both mouse MOR and DOR up to 10 &mu;M. This was confirmed at the human MOR and DOR in the [<sup>35</sup>S]GTP&gamma;S binding assay. We next determined the mechanism of antagonism of DNCP--NalA(1) by measuring adenylyl cyclase-mediated cAMP inhibition and [<sup>35</sup>S]GTP&gamma;S binding at mouse and human MOR, respectively, using Schild regression analysis. The MOR expressed in HEK293 and CHO cells was activated by DAMGO in the absence and presence of increasing concentrations of DNCP--NalA(1). We observed a rightward shift of the concentration-response curves of DAMGO in cAMP and [<sup>35</sup>S]GTP&gamma;S binding assays. Schild analysis of DNCP--NalA(1) exhibited linear regression slopes of 0.9 and 1.5 and pA2 values of 9.1 and 7.9 in cAMP and [<sup>35</sup>S]GTP&gamma;S binding assays, respectively, which corresponds to an average functional affinity of 0.8 and 13 nM, respectively, thus demonstrating the competitive antagonism of the DNCP--NalA(1) at MOR."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00125	Pain	Experiments were performed in male SWISS mice. Radioligand binding (n=3) and functional cAMP assays (n=3-4) of DNCP-beta-NalA conjugates were performed on HEK293T cell membranes stably expressing mouse KOR.	Discovered Using Cell Line-derived Xenograft Model	.	Half Maximal Effect Concentration (EC50)	1.7 &plusmn; 0.5 x 10<sup>-9</sup> mol	nM	.	.	.	.	.	.	.	.	.	.	.	"The TRUPATH screening platform has been developed as an alternative to cAMP second messenger assays to minimize signal overamplification35. Intriguingly, in contrast to U50,488 and MP1104, but similar to the mixed-action KOR agonist pentazocine, DNCP--NalA(1) exhibited KOR partial agonism at Gi2, Gi3, GoA, GoB and Ggastducin subtypes with Emax values ranging from 48% to 77%, whereas it elicited full agonism at Gi1 and Gz with Emax values of 81% and 101%, respectively. The highest potency in the picomolar range was observed at Gz subtype for DNCP--NalA(1), U50,488 and MP1104, while pentazocine revealed the least variation in potency and efficacy across the transducerome."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00125	Pain	Experiments were performed in male SWISS mice. Radioligand binding (n=3) and functional cAMP assays (n=3-4) of DNCP-beta-NalA conjugates were performed on HEK293T cell membranes stably expressing mouse KOR.	Discovered Using Cell Line-derived Xenograft Model	.	Half Maximal Effect Concentration (EC50)	0.9 &plusmn; 0.4 x 10<sup>-9</sup> mol	nM	.	.	.	.	.	.	.	.	.	.	.	"The TRUPATH screening platform has been developed as an alternative to cAMP second messenger assays to minimize signal overamplification35. Intriguingly, in contrast to U50,488 and MP1104, but similar to the mixed-action KOR agonist pentazocine, DNCP--NalA(1) exhibited KOR partial agonism at Gi2, Gi3, GoA, GoB and Ggastducin subtypes with Emax values ranging from 48% to 77%, whereas it elicited full agonism at Gi1 and Gz with Emax values of 81% and 101%, respectively. The highest potency in the picomolar range was observed at Gz subtype for DNCP--NalA(1), U50,488 and MP1104, while pentazocine revealed the least variation in potency and efficacy across the transducerome."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00125	Pain	Experiments were performed in male SWISS mice. Radioligand binding (n=3) and functional cAMP assays (n=3-4) of DNCP-beta-NalA conjugates were performed on HEK293T cell membranes stably expressing mouse KOR.	Discovered Using Cell Line-derived Xenograft Model	.	Half Maximal Effect Concentration (EC50)	0.7 &plusmn; 0.2 x 10<sup>-9</sup> mol	nM	.	.	.	.	.	.	.	.	.	.	.	"The TRUPATH screening platform has been developed as an alternative to cAMP second messenger assays to minimize signal overamplification35. Intriguingly, in contrast to U50,488 and MP1104, but similar to the mixed-action KOR agonist pentazocine, DNCP--NalA(1) exhibited KOR partial agonism at Gi2, Gi3, GoA, GoB and Ggastducin subtypes with Emax values ranging from 48% to 77%, whereas it elicited full agonism at Gi1 and Gz with Emax values of 81% and 101%, respectively. The highest potency in the picomolar range was observed at Gz subtype for DNCP--NalA(1), U50,488 and MP1104, while pentazocine revealed the least variation in potency and efficacy across the transducerome."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00125	Pain	Experiments were performed in male SWISS mice. Radioligand binding (n=3) and functional cAMP assays (n=3-4) of DNCP-beta-NalA conjugates were performed on HEK293T cell membranes stably expressing mouse KOR.	Discovered Using Cell Line-derived Xenograft Model	.	Half Maximal Effect Concentration (EC50)	3.1 &plusmn; 1.5 x 10<sup>-8</sup> mol	nM	.	.	.	.	.	.	.	.	.	.	.	"The TRUPATH screening platform has been developed as an alternative to cAMP second messenger assays to minimize signal overamplification35. Intriguingly, in contrast to U50,488 and MP1104, but similar to the mixed-action KOR agonist pentazocine, DNCP--NalA(1) exhibited KOR partial agonism at Gi2, Gi3, GoA, GoB and Ggastducin subtypes with Emax values ranging from 48% to 77%, whereas it elicited full agonism at Gi1 and Gz with Emax values of 81% and 101%, respectively. The highest potency in the picomolar range was observed at Gz subtype for DNCP--NalA(1), U50,488 and MP1104, while pentazocine revealed the least variation in potency and efficacy across the transducerome."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00125	Pain	Experiments were performed in male SWISS mice. Radioligand binding (n=3) and functional cAMP assays (n=3-4) of DNCP-beta-NalA conjugates were performed on HEK293T cell membranes stably expressing mouse KOR.	Discovered Using Cell Line-derived Xenograft Model	.	Half Maximal Effect Concentration (EC50)	2.4 &plusmn; 0.9 x 10<sup>-9</sup> mol	nM	.	.	.	.	.	.	.	.	.	.	.	"The TRUPATH screening platform has been developed as an alternative to cAMP second messenger assays to minimize signal overamplification35. Intriguingly, in contrast to U50,488 and MP1104, but similar to the mixed-action KOR agonist pentazocine, DNCP--NalA(1) exhibited KOR partial agonism at Gi2, Gi3, GoA, GoB and Ggastducin subtypes with Emax values ranging from 48% to 77%, whereas it elicited full agonism at Gi1 and Gz with Emax values of 81% and 101%, respectively. The highest potency in the picomolar range was observed at Gz subtype for DNCP--NalA(1), U50,488 and MP1104, while pentazocine revealed the least variation in potency and efficacy across the transducerome."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00125	Pain	Experiments were performed in male SWISS mice. Radioligand binding (n=3) and functional cAMP assays (n=3-4) of DNCP-beta-NalA conjugates were performed on HEK293T cell membranes stably expressing mouse KOR.	Discovered Using Cell Line-derived Xenograft Model	.	Half Maximal Effect Concentration (EC50)	0.1 &plusmn; 0.0 x 10<sup>-9</sup> mol	nM	.	.	.	.	.	.	.	.	.	.	.	"The TRUPATH screening platform has been developed as an alternative to cAMP second messenger assays to minimize signal overamplification35. Intriguingly, in contrast to U50,488 and MP1104, but similar to the mixed-action KOR agonist pentazocine, DNCP--NalA(1) exhibited KOR partial agonism at Gi2, Gi3, GoA, GoB and Ggastducin subtypes with Emax values ranging from 48% to 77%, whereas it elicited full agonism at Gi1 and Gz with Emax values of 81% and 101%, respectively. The highest potency in the picomolar range was observed at Gz subtype for DNCP--NalA(1), U50,488 and MP1104, while pentazocine revealed the least variation in potency and efficacy across the transducerome."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00287	PDC_00125	Pain	Experiments were performed in male SWISS mice. Radioligand binding (n=3) and functional cAMP assays (n=3-4) of DNCP-beta-NalA conjugates were performed on HEK293T cell membranes stably expressing mouse KOR.	Discovered Using Cell Line-derived Xenograft Model	.	Half Maximal Effect Concentration (EC50)	1.4 &plusmn; 0.3 x 10<sup>-9</sup> mol	nM	.	.	.	.	.	.	.	.	.	.	.	"The TRUPATH screening platform has been developed as an alternative to cAMP second messenger assays to minimize signal overamplification35. Intriguingly, in contrast to U50,488 and MP1104, but similar to the mixed-action KOR agonist pentazocine, DNCP--NalA(1) exhibited KOR partial agonism at Gi2, Gi3, GoA, GoB and Ggastducin subtypes with Emax values ranging from 48% to 77%, whereas it elicited full agonism at Gi1 and Gz with Emax values of 81% and 101%, respectively. The highest potency in the picomolar range was observed at Gz subtype for DNCP--NalA(1), U50,488 and MP1104, while pentazocine revealed the least variation in potency and efficacy across the transducerome."	"Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	5.6 months	months	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"In the overall alkylator-refractory group, the melflufen and pomalidomide arms saw a similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; HR, 0.92 [95% CI, 0.63-1.33]) and median OS (23.4 months [14.4-31.7] vs. 20.0 months [12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Corresponding results were observed when evaluating PFS and OS in subgroups by type of prior alkylating agent received. In the melflufen and pomalidomide arms, the ORR was 24.4% and 28.0% in patients refractory to alkylators overall, 22.2% and 25.0% in patients refractory to cyclophosphamide, and 33.3% and 26.1% in patients refractory to melphalan, respectively."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	23.4 months	months	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"In the overall alkylator-refractory group, the melflufen and pomalidomide arms saw a similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; HR, 0.92 [95% CI, 0.63-1.33]) and median OS (23.4 months [14.4-31.7] vs. 20.0 months [12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Corresponding results were observed when evaluating PFS and OS in subgroups by type of prior alkylating agent received. In the melflufen and pomalidomide arms, the ORR was 24.4% and 28.0% in patients refractory to alkylators overall, 22.2% and 25.0% in patients refractory to cyclophosphamide, and 33.3% and 26.1% in patients refractory to melphalan, respectively."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	73.74%	%	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	74.12%	%	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	73.47%	%	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	74.47%	%	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	73.68%	%	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	74.07%	%	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	73.97%	%	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Bleeding	100%	%	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Neutropenia	73.85%	%	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Infections	73.33%	%	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia concurrent with grade 3/4 bleeding	100%	%	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Neutropenia concurrent with grade 3/4 infection	100%	%	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Leukopenia	71.43%	%	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Time to dose reduction	106 Day	Day	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Time to grade 3/4 thrombocytopenia	52 Day	Day	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00284	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Time to grade 3/4 neutropenia	36 Day	Day	.	.	.	"153 patients refractory to prior alkylators (melflufen, n=78; pomalidomide, n=75)."	.	.	.	.	.	.	.	"Overall, the safety profile of melflufen plus dexamethasone in the alkylator-refractory group was consistent between treatment arms (Table 2). In the melflufen and pomalidomide arms, respectively, the frequency of treatment-emergent adverse events (TEAEs; 99% vs. 97%), Grade 3 or 4 TEAEs (85% vs. 82%), serious TEAEs (49% vs. 53%), and fatal TEAEs (19% vs. 16%) were similar (Table 2). However, melflufen compared with pomalidomide saw more dose modifications (76% vs. 67%) and dose reductions (47% vs. 14%), comparable dose delays (57% vs. 51%) but less treatment discontinuation (27% vs. 34%). When comparing patients refractory and not refractory to prior alkylators, rates of TEAEs were generally comparable except for slightly lower rates of serious and fatal TEAEs observed in patients not refractory to alkylators. Among Grade 3 or 4 TEAEs of special interest, melflufen saw more thrombocytopenia (73% vs. 14%), neutropenia (65% vs. 55%), and leukopenia or white blood cell decrease (14% vs. 3%), but less infection (15% vs. 26%), than pomalidomide. Notably, melflufen compared with pomalidomide saw a longer median time to dose reduction (106 days [range, 28-443] vs. 47 days [range, 28-225]), Grade 3 or 4 thrombocytopenia (52 days [range, 15-451] vs. 19 days [range, 8-91]), and Grade 3 or 4 neutropenia (36 days [range, 8-561] vs. 22 days [range, 8-470])."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2-8.3] vs. 4.7 months [95% CI, 3.1-7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63-1.33]) and OS (23.4 months [95% CI, 14.4-31.7] vs. 20.0 months [95% CI, 12.0-28.7]; HR, 0.92 [95% CI, 0.62-1.38]). Among alkylator-refractory patients with a TTP 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator-refractory disease, suggesting differentiated activity from other alkylators."
REF00283	PDC_00046	Primary malignant lung tumors	.	Identified from the Human Clinical Data	.	Area under the curve (AUC)	0.908	.	.	.	.	26 patients with primary malignant lung tumors.	.	.	.	.	40-50 minutes	11.1 MBq (0.3 mCi)/kg	.	"Total 42 stations had metastatic lymph nodes and 136 stations had benign lymph nodes. The differences between metastatic and benign lymph nodes in the visual qualitative and semiquantitative analyses of 99mTc-3PRGD2 SPECT/CT and 18F-FDG PET/CT were statistically significant (all P < 0.001). The area under the receiver operating characteristic curve (AUC) in the semi-quantitative analysis of 99mTc-3PRGD2 SPECT/CT was 0.908 (95% confidence interval [CI], 0.851-0.966), and the sensitivity, specificity, positive predictive value, and negative predictive value were 0.86 (36/42), 0.88 (120/136), 0.69 (36/52), and 0.95 (120/126), respectively. Among the 26 patients (including two patients each with two lung tumors), 15 had pathologically confirmed lymph node metastasis. The difference between primary lung lesions in patients with and without lymph node metastasis was statistically significant only in the semi-quantitative analysis of 99mTc-3PRGD2 SPECT/CT (P = 0.007), with an AUC of 0.807 (95% CI, 0.641-0.974)."	"The integrin v&beta;3 receptor is a transmembrane heterodimer that mediates cell-cell and cell-extracellular matrix adhesions. It is ubiquitously present during the development and progression of malignant tumors and is closely associated with angiogenesis and metastasis. This receptor is highly expressed in proliferating tumor cells and activated endothelial cells, but is either not expressed or expressed at very low levels in normal endothelial cells, dormant vascular cells, and other normal cells, exhibiting a certain specificity. 99mtechnetium-three polyethylene glycol spacers-arginine-glycine-aspartic acid (99mTc-3PRGD2) is a single-photon emission computed tomography (SPECT) imaging agent that targets the integrin v&beta;33 receptor. Previous studies have confirmed the feasibility of 99mTc-3PRGD2 SPECT imaging for the diagnosis of lung cancer, breast cancer, esophageal cancer, and other malignant tumors and their related lymph node metastases. This study aimed to further investigate the performance of 99mTc-3PRGD2 SPECT/CT imaging in the diagnosis of lymph node metastasis in primary malignant lung tumors by comparing it with 18F-FDG PET/CT imaging."
REF00283	PDC_00046	Primary malignant lung tumors	.	Identified from the Human Clinical Data	.	Sensitivity	85.71%	%	.	.	.	26 patients with primary malignant lung tumors.	.	.	.	.	40-50 minutes	11.1 MBq (0.3 mCi)/kg	.	"Total 42 stations had metastatic lymph nodes and 136 stations had benign lymph nodes. The differences between metastatic and benign lymph nodes in the visual qualitative and semiquantitative analyses of 99mTc-3PRGD2 SPECT/CT and 18F-FDG PET/CT were statistically significant (all P < 0.001). The area under the receiver operating characteristic curve (AUC) in the semi-quantitative analysis of 99mTc-3PRGD2 SPECT/CT was 0.908 (95% confidence interval [CI], 0.851-0.966), and the sensitivity, specificity, positive predictive value, and negative predictive value were 0.86 (36/42), 0.88 (120/136), 0.69 (36/52), and 0.95 (120/126), respectively. Among the 26 patients (including two patients each with two lung tumors), 15 had pathologically confirmed lymph node metastasis. The difference between primary lung lesions in patients with and without lymph node metastasis was statistically significant only in the semi-quantitative analysis of 99mTc-3PRGD2 SPECT/CT (P = 0.007), with an AUC of 0.807 (95% CI, 0.641-0.974)."	"The integrin v&beta;3 receptor is a transmembrane heterodimer that mediates cell-cell and cell-extracellular matrix adhesions. It is ubiquitously present during the development and progression of malignant tumors and is closely associated with angiogenesis and metastasis. This receptor is highly expressed in proliferating tumor cells and activated endothelial cells, but is either not expressed or expressed at very low levels in normal endothelial cells, dormant vascular cells, and other normal cells, exhibiting a certain specificity. 99mtechnetium-three polyethylene glycol spacers-arginine-glycine-aspartic acid (99mTc-3PRGD2) is a single-photon emission computed tomography (SPECT) imaging agent that targets the integrin v&beta;33 receptor. Previous studies have confirmed the feasibility of 99mTc-3PRGD2 SPECT imaging for the diagnosis of lung cancer, breast cancer, esophageal cancer, and other malignant tumors and their related lymph node metastases. This study aimed to further investigate the performance of 99mTc-3PRGD2 SPECT/CT imaging in the diagnosis of lymph node metastasis in primary malignant lung tumors by comparing it with 18F-FDG PET/CT imaging."
REF00283	PDC_00046	Primary malignant lung tumors	.	Identified from the Human Clinical Data	.	Specificity	88.24%	%	.	.	.	26 patients with primary malignant lung tumors.	.	.	.	.	40-50 minutes	11.1 MBq (0.3 mCi)/kg	.	"Total 42 stations had metastatic lymph nodes and 136 stations had benign lymph nodes. The differences between metastatic and benign lymph nodes in the visual qualitative and semiquantitative analyses of 99mTc-3PRGD2 SPECT/CT and 18F-FDG PET/CT were statistically significant (all P < 0.001). The area under the receiver operating characteristic curve (AUC) in the semi-quantitative analysis of 99mTc-3PRGD2 SPECT/CT was 0.908 (95% confidence interval [CI], 0.851-0.966), and the sensitivity, specificity, positive predictive value, and negative predictive value were 0.86 (36/42), 0.88 (120/136), 0.69 (36/52), and 0.95 (120/126), respectively. Among the 26 patients (including two patients each with two lung tumors), 15 had pathologically confirmed lymph node metastasis. The difference between primary lung lesions in patients with and without lymph node metastasis was statistically significant only in the semi-quantitative analysis of 99mTc-3PRGD2 SPECT/CT (P = 0.007), with an AUC of 0.807 (95% CI, 0.641-0.974)."	"The integrin v&beta;3 receptor is a transmembrane heterodimer that mediates cell-cell and cell-extracellular matrix adhesions. It is ubiquitously present during the development and progression of malignant tumors and is closely associated with angiogenesis and metastasis. This receptor is highly expressed in proliferating tumor cells and activated endothelial cells, but is either not expressed or expressed at very low levels in normal endothelial cells, dormant vascular cells, and other normal cells, exhibiting a certain specificity. 99mtechnetium-three polyethylene glycol spacers-arginine-glycine-aspartic acid (99mTc-3PRGD2) is a single-photon emission computed tomography (SPECT) imaging agent that targets the integrin v&beta;33 receptor. Previous studies have confirmed the feasibility of 99mTc-3PRGD2 SPECT imaging for the diagnosis of lung cancer, breast cancer, esophageal cancer, and other malignant tumors and their related lymph node metastases. This study aimed to further investigate the performance of 99mTc-3PRGD2 SPECT/CT imaging in the diagnosis of lymph node metastasis in primary malignant lung tumors by comparing it with 18F-FDG PET/CT imaging."
REF00279	PDC_00102	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	99.2 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	25.7 h	.	72 h	.	CCK-8 assay	"Besides, the combination of DTX and CTCE showed a substantially greater cytotoxicity, with an approximate 2 folds reduction (67.9 nmol/L) in half-maximal inhibitory concentration (IC50) compared to DTX alone. What's more, CTCE-DTX NPs retained a greater cytotoxicity (IC50 = 88.5 nmol/L) than Sc-DTX NPs (IC50 = 169.5 nmol/L), which meant CXCR4 antagonist peptide could work as a sensitizer to DTX. The slightly higher IC50 value of CTCE-DTX NPs than that of DTX + CTCE group may attribute to the incomplete disassembly of nanostructures. Meanwhile, consistent with previous reports14, the CXCR4 antagonist peptide and scramble peptide didn't not show any cytotoxicity to 4T1 cell at low concentration. We also tested the cytotoxicity of the formulations to another CXCR4 high expression (MDA-MB-231) and CXCR4 low expression (HepG2) cell lines and calculated the IC50. In MDA-MB-231 cell line, the IC50 of CTCE-DTX NPs (99.2 nmol/L) was significantly lower than that of DTX (135.8 nmol/L) and Sc-DTX NPs (250.1 nmol/L), which was consist with the tendency of formulations to 4T1 cell line. In comparison, in HepG2 cell line, the IC50 of CTCE-DTX NPs (166.8 nmol/L) was higher than that of DTX (109.5 nmol/L). The results further proved that the recognition of CTCE-DTX NPs with CXCR4 could enhance the cytotoxicity to tumor cells. These results demonstrated that CTCE peptide enhanced the chemosensitivity of cancer cell toward DTX but possessed with no direct toxicity."	"To increase the DTX solubility and avoid the DTX therapy induced metastasis, we designed a peptide-drug conjugate (CTCE-DTX) by coupling two functional molecules (CXCR4 antagonist peptide and chemotherapeutic agent DTX) through a flexible linker. The amphiphilic monomer of CTCE-DTX could self-assemble into nanoparticles (CTCE-DTX NPs) in the water environment (without the participation of toxic ethanol and Tween 80 as excipients). The CXCR4 antagonist component could target CXCR4 upregulated tumor cells, which not only enhanced the efficacy of DTX but also inhibited the bone and lung metastasis of TNBC."
REF00279	PDC_00103	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	250.1 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	29.3 h	.	72 h	.	CCK-8 assay	"Besides, the combination of DTX and CTCE showed a substantially greater cytotoxicity, with an approximate 2 folds reduction (67.9 nmol/L) in half-maximal inhibitory concentration (IC50) compared to DTX alone. What's more, CTCE-DTX NPs retained a greater cytotoxicity (IC50 = 88.5 nmol/L) than Sc-DTX NPs (IC50 = 169.5 nmol/L), which meant CXCR4 antagonist peptide could work as a sensitizer to DTX. The slightly higher IC50 value of CTCE-DTX NPs than that of DTX + CTCE group may attribute to the incomplete disassembly of nanostructures. Meanwhile, consistent with previous reports14, the CXCR4 antagonist peptide and scramble peptide didn't not show any cytotoxicity to 4T1 cell at low concentration. We also tested the cytotoxicity of the formulations to another CXCR4 high expression (MDA-MB-231) and CXCR4 low expression (HepG2) cell lines and calculated the IC50. In MDA-MB-231 cell line, the IC50 of CTCE-DTX NPs (99.2 nmol/L) was significantly lower than that of DTX (135.8 nmol/L) and Sc-DTX NPs (250.1 nmol/L), which was consist with the tendency of formulations to 4T1 cell line. In comparison, in HepG2 cell line, the IC50 of CTCE-DTX NPs (166.8 nmol/L) was higher than that of DTX (109.5 nmol/L). The results further proved that the recognition of CTCE-DTX NPs with CXCR4 could enhance the cytotoxicity to tumor cells. These results demonstrated that CTCE peptide enhanced the chemosensitivity of cancer cell toward DTX but possessed with no direct toxicity."	"To increase the DTX solubility and avoid the DTX therapy induced metastasis, we designed a peptide-drug conjugate (CTCE-DTX) by coupling two functional molecules (CXCR4 antagonist peptide and chemotherapeutic agent DTX) through a flexible linker. The amphiphilic monomer of CTCE-DTX could self-assemble into nanoparticles (CTCE-DTX NPs) in the water environment (without the participation of toxic ethanol and Tween 80 as excipients). The CXCR4 antagonist component could target CXCR4 upregulated tumor cells, which not only enhanced the efficacy of DTX but also inhibited the bone and lung metastasis of TNBC."
REF00279	PDC_00102	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	166.8 nM	nM	.	.	.	.	Hepatoblastoma	GPC3 positive HepG2 cell	25.7 h	.	72 h	.	CCK-8 assay	"Besides, the combination of DTX and CTCE showed a substantially greater cytotoxicity, with an approximate 2 folds reduction (67.9 nmol/L) in half-maximal inhibitory concentration (IC50) compared to DTX alone. What's more, CTCE-DTX NPs retained a greater cytotoxicity (IC50 = 88.5 nmol/L) than Sc-DTX NPs (IC50 = 169.5 nmol/L), which meant CXCR4 antagonist peptide could work as a sensitizer to DTX. The slightly higher IC50 value of CTCE-DTX NPs than that of DTX + CTCE group may attribute to the incomplete disassembly of nanostructures. Meanwhile, consistent with previous reports14, the CXCR4 antagonist peptide and scramble peptide didn't not show any cytotoxicity to 4T1 cell at low concentration. We also tested the cytotoxicity of the formulations to another CXCR4 high expression (MDA-MB-231) and CXCR4 low expression (HepG2) cell lines and calculated the IC50. In MDA-MB-231 cell line, the IC50 of CTCE-DTX NPs (99.2 nmol/L) was significantly lower than that of DTX (135.8 nmol/L) and Sc-DTX NPs (250.1 nmol/L), which was consist with the tendency of formulations to 4T1 cell line. In comparison, in HepG2 cell line, the IC50 of CTCE-DTX NPs (166.8 nmol/L) was higher than that of DTX (109.5 nmol/L). The results further proved that the recognition of CTCE-DTX NPs with CXCR4 could enhance the cytotoxicity to tumor cells. These results demonstrated that CTCE peptide enhanced the chemosensitivity of cancer cell toward DTX but possessed with no direct toxicity."	"To increase the DTX solubility and avoid the DTX therapy induced metastasis, we designed a peptide-drug conjugate (CTCE-DTX) by coupling two functional molecules (CXCR4 antagonist peptide and chemotherapeutic agent DTX) through a flexible linker. The amphiphilic monomer of CTCE-DTX could self-assemble into nanoparticles (CTCE-DTX NPs) in the water environment (without the participation of toxic ethanol and Tween 80 as excipients). The CXCR4 antagonist component could target CXCR4 upregulated tumor cells, which not only enhanced the efficacy of DTX but also inhibited the bone and lung metastasis of TNBC."
REF00279	PDC_00103	Liver cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	206.0 nM	nM	.	.	.	.	Hepatoblastoma	GPC3 positive HepG2 cell	29.3 h	.	72 h	.	CCK-8 assay	"Besides, the combination of DTX and CTCE showed a substantially greater cytotoxicity, with an approximate 2 folds reduction (67.9 nmol/L) in half-maximal inhibitory concentration (IC50) compared to DTX alone. What's more, CTCE-DTX NPs retained a greater cytotoxicity (IC50 = 88.5 nmol/L) than Sc-DTX NPs (IC50 = 169.5 nmol/L), which meant CXCR4 antagonist peptide could work as a sensitizer to DTX. The slightly higher IC50 value of CTCE-DTX NPs than that of DTX + CTCE group may attribute to the incomplete disassembly of nanostructures. Meanwhile, consistent with previous reports14, the CXCR4 antagonist peptide and scramble peptide didn't not show any cytotoxicity to 4T1 cell at low concentration. We also tested the cytotoxicity of the formulations to another CXCR4 high expression (MDA-MB-231) and CXCR4 low expression (HepG2) cell lines and calculated the IC50. In MDA-MB-231 cell line, the IC50 of CTCE-DTX NPs (99.2 nmol/L) was significantly lower than that of DTX (135.8 nmol/L) and Sc-DTX NPs (250.1 nmol/L), which was consist with the tendency of formulations to 4T1 cell line. In comparison, in HepG2 cell line, the IC50 of CTCE-DTX NPs (166.8 nmol/L) was higher than that of DTX (109.5 nmol/L). The results further proved that the recognition of CTCE-DTX NPs with CXCR4 could enhance the cytotoxicity to tumor cells. These results demonstrated that CTCE peptide enhanced the chemosensitivity of cancer cell toward DTX but possessed with no direct toxicity."	"To increase the DTX solubility and avoid the DTX therapy induced metastasis, we designed a peptide-drug conjugate (CTCE-DTX) by coupling two functional molecules (CXCR4 antagonist peptide and chemotherapeutic agent DTX) through a flexible linker. The amphiphilic monomer of CTCE-DTX could self-assemble into nanoparticles (CTCE-DTX NPs) in the water environment (without the participation of toxic ethanol and Tween 80 as excipients). The CXCR4 antagonist component could target CXCR4 upregulated tumor cells, which not only enhanced the efficacy of DTX but also inhibited the bone and lung metastasis of TNBC."
REF00278	PDC_00225	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.18 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00226	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.17 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00227	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.15 &plusmn; 0.03 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00228	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.14 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00229	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.19 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00230	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.18 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00231	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.11 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00232	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.14 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00225	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.57 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Gastric carcinoma	SGC-7901 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00226	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.51 &plusmn; 0.03 &micro;M	&micro;M	.	.	.	.	Gastric carcinoma	SGC-7901 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00227	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.46 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Gastric carcinoma	SGC-7901 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00228	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.38 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Gastric carcinoma	SGC-7901 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00229	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.54 &plusmn; 0.03 &micro;M	&micro;M	.	.	.	.	Gastric carcinoma	SGC-7901 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00230	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.41 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Gastric carcinoma	SGC-7901 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00231	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.33 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Gastric carcinoma	SGC-7901 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00232	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.47 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Gastric carcinoma	SGC-7901 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00225	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.59 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00226	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.50 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00227	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.42 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00228	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.43 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00229	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.51 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00230	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.51 &plusmn; 0.04 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00231	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.42 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00232	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.41 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00225	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.45 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT-116/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00226	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.47 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT-116/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00227	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.35 &plusmn; 0.03 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT-116/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00228	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.32 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT-116/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00229	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.46 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT-116/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00230	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.44 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT-116/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00231	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.23 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT-116/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00232	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.35 &plusmn; 0.02 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT-116/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00225	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.34 &plusmn; 0.12 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	SGC-7901/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00226	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.23 &plusmn; 0.10 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	SGC-7901/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00227	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.19 &plusmn; 0.06 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	SGC-7901/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00228	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.00 &plusmn; 0.08 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	SGC-7901/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00229	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.20 &plusmn; 0.10 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	SGC-7901/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00230	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.02 &plusmn; 0.11 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	SGC-7901/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00231	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.80 &plusmn; 0.08 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	SGC-7901/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00232	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.06 &plusmn; 0.07 &micro;M	&micro;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	SGC-7901/CPT cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00225	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.48 &plusmn; 0.18 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma of no special type	MCF7/C4 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00226	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.26 &plusmn; 0.11 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma of no special type	MCF7/C4 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00227	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.03 &plusmn; 0.03 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma of no special type	MCF7/C4 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00228	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.05 &plusmn; 0.03 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma of no special type	MCF7/C4 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00229	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.18 &plusmn; 0.10 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma of no special type	MCF7/C4 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00230	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.20 &plusmn; 0.13 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma of no special type	MCF7/C4 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00231	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.01 &plusmn; 0.05 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma of no special type	MCF7/C4 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00232	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.03 &plusmn; 0.06 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma of no special type	MCF7/C4 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00225	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	14.0 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Normal	NCM460 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00226	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	15.4 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Normal	NCM460 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00227	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	13.3 &plusmn; 1.0 &micro;M	&micro;M	.	.	.	.	Normal	NCM460 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00228	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	13.4 &plusmn; 0.4 &micro;M	&micro;M	.	.	.	.	Normal	NCM460 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00229	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	16.2 &plusmn; 1.0 &micro;M	&micro;M	.	.	.	.	Normal	NCM460 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00230	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	15.1 &plusmn; 0.4 &micro;M	&micro;M	.	.	.	.	Normal	NCM460 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00231	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	13.7 &plusmn; 1.1 &micro;M	&micro;M	.	.	.	.	Normal	NCM460 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00232	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	14.8 &plusmn; 0.9 &micro;M	&micro;M	.	.	.	.	Normal	NCM460 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00225	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	15.5 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Normal	GES1 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00226	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	14.4 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Normal	GES1 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00227	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	14.9 &plusmn; 0.9 &micro;M	&micro;M	.	.	.	.	Normal	GES1 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00228	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	15.5 &plusmn; 0.6 &micro;M	&micro;M	.	.	.	.	Normal	GES1 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00229	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	16.0 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Normal	GES1 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00230	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	16.0 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	Normal	GES1 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00231	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	17.3 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	Normal	GES1 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00232	Gastric cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	15.2 &plusmn; 0.7 &micro;M	&micro;M	.	.	.	.	Normal	GES1 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00225	Liver cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	15.0 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	LO #2 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00226	Liver cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	15.4 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	LO #2 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00227	Liver cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	17.3 &plusmn; 0.8 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	LO #2 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00228	Liver cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	16.4 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	LO #2 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00229	Liver cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	15.6 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	LO #2 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00230	Liver cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	16.3 &plusmn; 0.4 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	LO #2 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00231	Liver cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	15.5 &plusmn; 1.0 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	LO #2 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00278	PDC_00232	Liver cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	16.1 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	LO #2 cell	.	.	48 h	.	MTT assay	"MTT assay was preformed to measure the in vitro cytotoxicities of the compounds against cancer cells (HCT-116, SGC-7901, MCF-7, HCT-116/CPT, SGC-7901/CPT and MCF-7/C4) and benign cells (NCM460, GES-1 and LO2). As present in Table 1, all the peptides (Kb-C01, 0207) exhibited certain selective anticancer activities, which are comparable to their parent counterpart KM8-Aib. The target PDCs (Kb-CC01, 0207) were further obtained by coupling the peptides with CPT, displaying markedly improved antiproliferative activities and selectivities against cancer cell lines over CPT. Studies have revealed that cancer cell membranes are negatively charged due to the presence of substantial amounts of acid phospholipids. Therefore, positively charged CAPs are capable of binding to cancer cell surface through electrostatic interactions, making them specific to cancer cells. In this project, since the PDCs were composed of CAP KM8-Aib and CPT, they potentially inherited the antineoplastic activities of KM8-Aib against cancer cells, as well as low toxicities to non-malignant cells."	"Cationic anticancer peptides (CAPs) refer to peptide-based molecules possessing a net positive charge, allowing them to preferentially combined with cancer cells which exhibit an overabundance of anionic components on their surface. Cationic peptides additionally induce cell membrane destabilization through carpet-like, toroidal pore or sinking raft et al. mechanism, or penetrate cell membrane and act on cellular sub-structures. Besides, cell-penetrating peptides (CPPs) represent a special subset of CAPs, renowned for their rapid and low-toxic cellular translocation abilities, making them promising vehicles for drug delivery. Therefore, CAPs are emerging as a class of potential anticancer agents and gaining widespread attention by researchers. As reported, the construction of bioactive peptides with cytotoxic payloads via a chemical linker provides a kind of prodrugs known as peptide-drug conjugates (PDCs), which represents an efficient approach to address the limitations of small molecules by leveraging the properties of peptides. In previous study, we have discovered the CAP of KM8-Aib (sequence: Lys-Leu-Leu-Lys-Lys-Asn-Leu-Lys-Aib-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2), which derived from venom peptide Mastoparan, exhibiting favorable antiproliferative effect against several cancer cells but less toxic to benign cells. Herein, we attempted to integrate CPT with KM8-Aib, obtaining a series of peptide-CPT conjugates, to improve the solubility, selectivity of CPT, and achieve enhanced therapeutic outcomes. Based on preliminary in vitro assays, the PDC Kb-CC07 demonstrated exceptional selective cytotoxicity against various cancer cell lines, including drug-resistant variants, surpassing that of other conjugates. The solubility of Kb-CC07 was also significantly increased, which is &tilde; 100 fold higher than that of CPT. In addition, we evaluated the in vivo antitumor efficacy of Kb-CC07 via nude-xenograft model. It is showed that mice treated with Kb-CC07 had substantially lower tumor volumes and minimum organ toxicities than CPT-treated group. As such, Kb-CC07 is suggested to be a promising anticancer agent and warrant thorough exploration."
REF00276	PDC_00212	Retinal injury	Brown norway rat optic nerve head (ONH) crush model.	Obtained from the Model Organism Data	.	RGC survival	869.2 &plusmn; 58.86 RGCs/mm<sup>2</sup>	RGCs/mm<sup>2</sup>	.	.	.	.	.	.	.	.	2 week	.	.	"We next tested the potential duration of neuroprotection after topical dosing of HR97-SunitiGel. Brown Norway rats were dosed with HR97-SunitiGel or SunitiGel daily for 7 days, the optic nerve head crush procedure was performed on day 0, 7, or 21 after the last topical dose, and the RGC survival was characterized 7 days after the injury. The RGC quantification results computed by the cell counting program showed that the neuroprotective effect of HR97-SunitiGel lasted for at least 2 weeks after the last dose (869.2 &plusmn; 58.86 RGCs/mm2 compared to sham, 623.7 &plusmn; 70.39 RGCs/mm2), with the effect waning 4 weeks after the last dose (692.2 &plusmn; 96.58 RGCs/mm2). In contrast, SunitiGel provided significant RGC protection at 1 week (846.4 &plusmn; 125.8 RGCs/mm2) compared to the sham group, with protection waning 2 weeks after the last dose (717.3 &plusmn; 59.94 RGCs/mm2)."	"In this work, we hypothesized that conjugation of the engineered multifunctional peptide adaptors to sunitinib for delivery to the posterior segment using the gel-forming eye drop would provide even more prolong therapeutic effects in the posterior tissues. We observed that the HR97-sunitinib conjugate had increased binding capacity to ocular melanin and was cleaved by proteases to release free sunitinib in vitro. Rats were dosed topically with HR97-SunitiGel once daily for seven days, followed by optic nerve head crush at various times after the last dose to assess the duration of RGC protection. We observed that the HR97-SunitiGel showed prolonged neuroprotective effects for up to 2 weeks after the last topical dose, whereas the protective effect of SunitiGel was only observed at 1 week after the last dose. Our observations support the potential for improving and prolonging therapeutic delivery to the posterior segment tissues by addressing multiple barriers to drug delivery and retention in the eye."
REF00276	PDC_00212	Retinal injury	Brown norway rat optic nerve head (ONH) crush model.	Obtained from the Model Organism Data	.	RGC survival	692.2 &plusmn; 96.58 RGCs/mm<sup>2</sup>	RGCs/mm<sup>2</sup>	.	.	.	.	.	.	.	.	4 week	.	.	"We next tested the potential duration of neuroprotection after topical dosing of HR97-SunitiGel. Brown Norway rats were dosed with HR97-SunitiGel or SunitiGel daily for 7 days, the optic nerve head crush procedure was performed on day 0, 7, or 21 after the last topical dose, and the RGC survival was characterized 7 days after the injury. The RGC quantification results computed by the cell counting program showed that the neuroprotective effect of HR97-SunitiGel lasted for at least 2 weeks after the last dose (869.2 &plusmn; 58.86 RGCs/mm2 compared to sham, 623.7 &plusmn; 70.39 RGCs/mm2), with the effect waning 4 weeks after the last dose (692.2 &plusmn; 96.58 RGCs/mm2). In contrast, SunitiGel provided significant RGC protection at 1 week (846.4 &plusmn; 125.8 RGCs/mm2) compared to the sham group, with protection waning 2 weeks after the last dose (717.3 &plusmn; 59.94 RGCs/mm2)."	"In this work, we hypothesized that conjugation of the engineered multifunctional peptide adaptors to sunitinib for delivery to the posterior segment using the gel-forming eye drop would provide even more prolong therapeutic effects in the posterior tissues. We observed that the HR97-sunitinib conjugate had increased binding capacity to ocular melanin and was cleaved by proteases to release free sunitinib in vitro. Rats were dosed topically with HR97-SunitiGel once daily for seven days, followed by optic nerve head crush at various times after the last dose to assess the duration of RGC protection. We observed that the HR97-SunitiGel showed prolonged neuroprotective effects for up to 2 weeks after the last topical dose, whereas the protective effect of SunitiGel was only observed at 1 week after the last dose. Our observations support the potential for improving and prolonging therapeutic delivery to the posterior segment tissues by addressing multiple barriers to drug delivery and retention in the eye."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	27 Intent-to-treat (ITT) population.	Identified from the Human Clinical Data	High Expreesion	Best confirmed response	4%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"In the ITT population, with a median follow-up of 7.1 months in the melflufen group, the median PFS was not reached (NR) and with a median follow-up of 6.6 months in the daratumumab group, the median PFS was 4.9 months (95% CI: 3.4-NR; HR: 0.18 [95% CI: 0.05-0.65]; log-rankP=0.0032). OS was immature, with 2 events (7%) in the melflufen group and 4 events (15%) in the daratumumab group (HR: 0.47 [95% CI: 0.09-2.57]; log-rankP=0.3721) at a median follow-up of 7.6 months and 6.6 months, respectively. The ORR was 59% (95% CI: 39-78) in the melflufen group and 30% (95% CI: 14-50) in the daratumumab group (P=0.0300). More patients in the melflufen group had a complete response (CR; 1 patient [4%]vs. 0 patients [0%]) and very good partial response (VGPR; 4 patients [15%]vs. 3 patients [11%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	27 Intent-to-treat (ITT) population.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	15%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"In the ITT population, with a median follow-up of 7.1 months in the melflufen group, the median PFS was not reached (NR) and with a median follow-up of 6.6 months in the daratumumab group, the median PFS was 4.9 months (95% CI: 3.4-NR; HR: 0.18 [95% CI: 0.05-0.65]; log-rankP=0.0032). OS was immature, with 2 events (7%) in the melflufen group and 4 events (15%) in the daratumumab group (HR: 0.47 [95% CI: 0.09-2.57]; log-rankP=0.3721) at a median follow-up of 7.6 months and 6.6 months, respectively. The ORR was 59% (95% CI: 39-78) in the melflufen group and 30% (95% CI: 14-50) in the daratumumab group (P=0.0300). More patients in the melflufen group had a complete response (CR; 1 patient [4%]vs. 0 patients [0%]) and very good partial response (VGPR; 4 patients [15%]vs. 3 patients [11%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	27 Intent-to-treat (ITT) population.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	41%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"In the ITT population, with a median follow-up of 7.1 months in the melflufen group, the median PFS was not reached (NR) and with a median follow-up of 6.6 months in the daratumumab group, the median PFS was 4.9 months (95% CI: 3.4-NR; HR: 0.18 [95% CI: 0.05-0.65]; log-rankP=0.0032). OS was immature, with 2 events (7%) in the melflufen group and 4 events (15%) in the daratumumab group (HR: 0.47 [95% CI: 0.09-2.57]; log-rankP=0.3721) at a median follow-up of 7.6 months and 6.6 months, respectively. The ORR was 59% (95% CI: 39-78) in the melflufen group and 30% (95% CI: 14-50) in the daratumumab group (P=0.0300). More patients in the melflufen group had a complete response (CR; 1 patient [4%]vs. 0 patients [0%]) and very good partial response (VGPR; 4 patients [15%]vs. 3 patients [11%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	27 Intent-to-treat (ITT) population.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	11%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"In the ITT population, with a median follow-up of 7.1 months in the melflufen group, the median PFS was not reached (NR) and with a median follow-up of 6.6 months in the daratumumab group, the median PFS was 4.9 months (95% CI: 3.4-NR; HR: 0.18 [95% CI: 0.05-0.65]; log-rankP=0.0032). OS was immature, with 2 events (7%) in the melflufen group and 4 events (15%) in the daratumumab group (HR: 0.47 [95% CI: 0.09-2.57]; log-rankP=0.3721) at a median follow-up of 7.6 months and 6.6 months, respectively. The ORR was 59% (95% CI: 39-78) in the melflufen group and 30% (95% CI: 14-50) in the daratumumab group (P=0.0300). More patients in the melflufen group had a complete response (CR; 1 patient [4%]vs. 0 patients [0%]) and very good partial response (VGPR; 4 patients [15%]vs. 3 patients [11%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	27 Intent-to-treat (ITT) population.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	11%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"In the ITT population, with a median follow-up of 7.1 months in the melflufen group, the median PFS was not reached (NR) and with a median follow-up of 6.6 months in the daratumumab group, the median PFS was 4.9 months (95% CI: 3.4-NR; HR: 0.18 [95% CI: 0.05-0.65]; log-rankP=0.0032). OS was immature, with 2 events (7%) in the melflufen group and 4 events (15%) in the daratumumab group (HR: 0.47 [95% CI: 0.09-2.57]; log-rankP=0.3721) at a median follow-up of 7.6 months and 6.6 months, respectively. The ORR was 59% (95% CI: 39-78) in the melflufen group and 30% (95% CI: 14-50) in the daratumumab group (P=0.0300). More patients in the melflufen group had a complete response (CR; 1 patient [4%]vs. 0 patients [0%]) and very good partial response (VGPR; 4 patients [15%]vs. 3 patients [11%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	27 Intent-to-treat (ITT) population.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	4%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"In the ITT population, with a median follow-up of 7.1 months in the melflufen group, the median PFS was not reached (NR) and with a median follow-up of 6.6 months in the daratumumab group, the median PFS was 4.9 months (95% CI: 3.4-NR; HR: 0.18 [95% CI: 0.05-0.65]; log-rankP=0.0032). OS was immature, with 2 events (7%) in the melflufen group and 4 events (15%) in the daratumumab group (HR: 0.47 [95% CI: 0.09-2.57]; log-rankP=0.3721) at a median follow-up of 7.6 months and 6.6 months, respectively. The ORR was 59% (95% CI: 39-78) in the melflufen group and 30% (95% CI: 14-50) in the daratumumab group (P=0.0300). More patients in the melflufen group had a complete response (CR; 1 patient [4%]vs. 0 patients [0%]) and very good partial response (VGPR; 4 patients [15%]vs. 3 patients [11%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	27 Intent-to-treat (ITT) population.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	15%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"In the ITT population, with a median follow-up of 7.1 months in the melflufen group, the median PFS was not reached (NR) and with a median follow-up of 6.6 months in the daratumumab group, the median PFS was 4.9 months (95% CI: 3.4-NR; HR: 0.18 [95% CI: 0.05-0.65]; log-rankP=0.0032). OS was immature, with 2 events (7%) in the melflufen group and 4 events (15%) in the daratumumab group (HR: 0.47 [95% CI: 0.09-2.57]; log-rankP=0.3721) at a median follow-up of 7.6 months and 6.6 months, respectively. The ORR was 59% (95% CI: 39-78) in the melflufen group and 30% (95% CI: 14-50) in the daratumumab group (P=0.0300). More patients in the melflufen group had a complete response (CR; 1 patient [4%]vs. 0 patients [0%]) and very good partial response (VGPR; 4 patients [15%]vs. 3 patients [11%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	27 Intent-to-treat (ITT) population.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	59% (39-78)	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"In the ITT population, with a median follow-up of 7.1 months in the melflufen group, the median PFS was not reached (NR) and with a median follow-up of 6.6 months in the daratumumab group, the median PFS was 4.9 months (95% CI: 3.4-NR; HR: 0.18 [95% CI: 0.05-0.65]; log-rankP=0.0032). OS was immature, with 2 events (7%) in the melflufen group and 4 events (15%) in the daratumumab group (HR: 0.47 [95% CI: 0.09-2.57]; log-rankP=0.3721) at a median follow-up of 7.6 months and 6.6 months, respectively. The ORR was 59% (95% CI: 39-78) in the melflufen group and 30% (95% CI: 14-50) in the daratumumab group (P=0.0300). More patients in the melflufen group had a complete response (CR; 1 patient [4%]vs. 0 patients [0%]) and very good partial response (VGPR; 4 patients [15%]vs. 3 patients [11%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Best confirmed response	7%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	14 patients no prior ASCT or TTP >36 months after ASCT.	.	.	.	.	.	.	.	"Efficacy endpoints were more pronounced in favor of the melflufen group compared with the daratumumab group among patients with no prior ASCT or TTP >36 months after a prior ASCT (melflufen group, N=14; daratumumab group, N=15). Median PFS was NR in the melflufen group and 3.9 months (95% CI: 1.4-4.9) in the daratumumab group (HR, 0.06 [95% CI: 0.01-0.49]; log-rank P=0.0005). Fewer OS events were reported in the melflufen group (1 event [7%] vs. 4 events [27%] in the daratumumab group; log-rank P=0.0369). The ORR was 64% (95% CI: 35-87) in the melflufen group and 13% (95% CI: 2-41) in the daratumumab group (P=0.0055). More patients in the melflufen group had a CR (1 patient [7%] vs. 0 patients [0%]) or VGPR (2 patients [14%] vs. 1 patient [7%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	14%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	14 patients no prior ASCT or TTP >36 months after ASCT.	.	.	.	.	.	.	.	"Efficacy endpoints were more pronounced in favor of the melflufen group compared with the daratumumab group among patients with no prior ASCT or TTP >36 months after a prior ASCT (melflufen group, N=14; daratumumab group, N=15). Median PFS was NR in the melflufen group and 3.9 months (95% CI: 1.4-4.9) in the daratumumab group (HR, 0.06 [95% CI: 0.01-0.49]; log-rank P=0.0005). Fewer OS events were reported in the melflufen group (1 event [7%] vs. 4 events [27%] in the daratumumab group; log-rank P=0.0369). The ORR was 64% (95% CI: 35-87) in the melflufen group and 13% (95% CI: 2-41) in the daratumumab group (P=0.0055). More patients in the melflufen group had a CR (1 patient [7%] vs. 0 patients [0%]) or VGPR (2 patients [14%] vs. 1 patient [7%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	43%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	14 patients no prior ASCT or TTP >36 months after ASCT.	.	.	.	.	.	.	.	"Efficacy endpoints were more pronounced in favor of the melflufen group compared with the daratumumab group among patients with no prior ASCT or TTP >36 months after a prior ASCT (melflufen group, N=14; daratumumab group, N=15). Median PFS was NR in the melflufen group and 3.9 months (95% CI: 1.4-4.9) in the daratumumab group (HR, 0.06 [95% CI: 0.01-0.49]; log-rank P=0.0005). Fewer OS events were reported in the melflufen group (1 event [7%] vs. 4 events [27%] in the daratumumab group; log-rank P=0.0369). The ORR was 64% (95% CI: 35-87) in the melflufen group and 13% (95% CI: 2-41) in the daratumumab group (P=0.0055). More patients in the melflufen group had a CR (1 patient [7%] vs. 0 patients [0%]) or VGPR (2 patients [14%] vs. 1 patient [7%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	14%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	14 patients no prior ASCT or TTP >36 months after ASCT.	.	.	.	.	.	.	.	"Efficacy endpoints were more pronounced in favor of the melflufen group compared with the daratumumab group among patients with no prior ASCT or TTP >36 months after a prior ASCT (melflufen group, N=14; daratumumab group, N=15). Median PFS was NR in the melflufen group and 3.9 months (95% CI: 1.4-4.9) in the daratumumab group (HR, 0.06 [95% CI: 0.01-0.49]; log-rank P=0.0005). Fewer OS events were reported in the melflufen group (1 event [7%] vs. 4 events [27%] in the daratumumab group; log-rank P=0.0369). The ORR was 64% (95% CI: 35-87) in the melflufen group and 13% (95% CI: 2-41) in the daratumumab group (P=0.0055). More patients in the melflufen group had a CR (1 patient [7%] vs. 0 patients [0%]) or VGPR (2 patients [14%] vs. 1 patient [7%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Minor response (MR)	0%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	14 patients no prior ASCT or TTP >36 months after ASCT.	.	.	.	.	.	.	.	"Efficacy endpoints were more pronounced in favor of the melflufen group compared with the daratumumab group among patients with no prior ASCT or TTP >36 months after a prior ASCT (melflufen group, N=14; daratumumab group, N=15). Median PFS was NR in the melflufen group and 3.9 months (95% CI: 1.4-4.9) in the daratumumab group (HR, 0.06 [95% CI: 0.01-0.49]; log-rank P=0.0005). Fewer OS events were reported in the melflufen group (1 event [7%] vs. 4 events [27%] in the daratumumab group; log-rank P=0.0369). The ORR was 64% (95% CI: 35-87) in the melflufen group and 13% (95% CI: 2-41) in the daratumumab group (P=0.0055). More patients in the melflufen group had a CR (1 patient [7%] vs. 0 patients [0%]) or VGPR (2 patients [14%] vs. 1 patient [7%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	7%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	14 patients no prior ASCT or TTP >36 months after ASCT.	.	.	.	.	.	.	.	"Efficacy endpoints were more pronounced in favor of the melflufen group compared with the daratumumab group among patients with no prior ASCT or TTP >36 months after a prior ASCT (melflufen group, N=14; daratumumab group, N=15). Median PFS was NR in the melflufen group and 3.9 months (95% CI: 1.4-4.9) in the daratumumab group (HR, 0.06 [95% CI: 0.01-0.49]; log-rank P=0.0005). Fewer OS events were reported in the melflufen group (1 event [7%] vs. 4 events [27%] in the daratumumab group; log-rank P=0.0369). The ORR was 64% (95% CI: 35-87) in the melflufen group and 13% (95% CI: 2-41) in the daratumumab group (P=0.0055). More patients in the melflufen group had a CR (1 patient [7%] vs. 0 patients [0%]) or VGPR (2 patients [14%] vs. 1 patient [7%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Progressive Disease (PD)	14%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	14 patients no prior ASCT or TTP >36 months after ASCT.	.	.	.	.	.	.	.	"Efficacy endpoints were more pronounced in favor of the melflufen group compared with the daratumumab group among patients with no prior ASCT or TTP >36 months after a prior ASCT (melflufen group, N=14; daratumumab group, N=15). Median PFS was NR in the melflufen group and 3.9 months (95% CI: 1.4-4.9) in the daratumumab group (HR, 0.06 [95% CI: 0.01-0.49]; log-rank P=0.0005). Fewer OS events were reported in the melflufen group (1 event [7%] vs. 4 events [27%] in the daratumumab group; log-rank P=0.0369). The ORR was 64% (95% CI: 35-87) in the melflufen group and 13% (95% CI: 2-41) in the daratumumab group (P=0.0055). More patients in the melflufen group had a CR (1 patient [7%] vs. 0 patients [0%]) or VGPR (2 patients [14%] vs. 1 patient [7%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	64% (35-87)	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	14 patients no prior ASCT or TTP >36 months after ASCT.	.	.	.	.	.	.	.	"Efficacy endpoints were more pronounced in favor of the melflufen group compared with the daratumumab group among patients with no prior ASCT or TTP >36 months after a prior ASCT (melflufen group, N=14; daratumumab group, N=15). Median PFS was NR in the melflufen group and 3.9 months (95% CI: 1.4-4.9) in the daratumumab group (HR, 0.06 [95% CI: 0.01-0.49]; log-rank P=0.0005). Fewer OS events were reported in the melflufen group (1 event [7%] vs. 4 events [27%] in the daratumumab group; log-rank P=0.0369). The ORR was 64% (95% CI: 35-87) in the melflufen group and 13% (95% CI: 2-41) in the daratumumab group (P=0.0055). More patients in the melflufen group had a CR (1 patient [7%] vs. 0 patients [0%]) or VGPR (2 patients [14%] vs. 1 patient [7%]) compared with the daratumumab group."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	22 relapsed/refractory multiple myeloma.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	96%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"The safety population included patients who received &ge;1 dose of melflufen, daratumumab, or dexamethasone (melflufen group) and 26 patients who received daratumumab monotherapy. In the safety population, &ge;1 TEAE was reported in 21 patients (96%) with melflufen, daratumumab, and dexamethasone and 22 patients (85%) with daratumumab. Overall, grade &ge;3 TEAE occurred in 18 patients (82%) with melflufen, daratumumab, and dexamethasone and 14 patients (54%) with daratumumab. The most common hematologic grade &ge;3 TEAE were neutropenia (melflufen group, 11 patients [50%]; daratumumab group, 3 patients [12%]), thrombocytopenia (melflufen group, 11 patients [50%]; daratumumab group, 2 patients [8%]), and anemia (melflufen group, 7 patients [32%]; daratumumab group, 5 patients [19%]). The most common non-hematologic grade &ge;3 TEAE were pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]) and femur fracture (melflufen group, 0 patients [0%]; daratumumab group, 2 patients [8%]); of these, 1 event (5%) of pneumonia in the melflufen group and 1 event (4%) of femur fracture in the daratumumab group were considered treatment-related TEAE by the investigator. Serious AE occurred in 6 patients (27%) with melflufen, daratumumab, and dexamethasone, and 12 patients (46%) with daratumumab. The most common serious AE (occurring in &ge;4 patients overall) were anemia (melflufen group, 2 patients [9%]; daratumumab group, 3 patients [12%]) and pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]). TEAE leading to treatment discontinuation occurred in 2 patients (9%) in the melflufen group (neutropenia and thrombocytopenia, N=1 each) and 4 patients (15%) in the daratumumab group (anemia, disease progression, hypercalcemia, and renal failure, N=1 each). Overall, 5 patients died on study before the crossover: 2 patients who received melflufen, daratumumab, and dexamethasone (1 due to disease progression and 1 due to unknown reasons, both >30 days after the last dose of study treatment) and 3 patients who received daratumumab (1 due to disease progression and 1 due to unknown reasons, both &le;30 days after the last dose of study treatment and 1 due to an AE [COVID-19 pneumonia], >30 days after the last dose of study treatment). In addition, one patient who crossed over to receive melflufen, daratumumab, and dexamethasone after progression on daratumumab died."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	22 relapsed/refractory multiple myeloma.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event rate	82%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"The safety population included patients who received &ge;1 dose of melflufen, daratumumab, or dexamethasone (melflufen group) and 26 patients who received daratumumab monotherapy. In the safety population, &ge;1 TEAE was reported in 21 patients (96%) with melflufen, daratumumab, and dexamethasone and 22 patients (85%) with daratumumab. Overall, grade &ge;3 TEAE occurred in 18 patients (82%) with melflufen, daratumumab, and dexamethasone and 14 patients (54%) with daratumumab. The most common hematologic grade &ge;3 TEAE were neutropenia (melflufen group, 11 patients [50%]; daratumumab group, 3 patients [12%]), thrombocytopenia (melflufen group, 11 patients [50%]; daratumumab group, 2 patients [8%]), and anemia (melflufen group, 7 patients [32%]; daratumumab group, 5 patients [19%]). The most common non-hematologic grade &ge;3 TEAE were pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]) and femur fracture (melflufen group, 0 patients [0%]; daratumumab group, 2 patients [8%]); of these, 1 event (5%) of pneumonia in the melflufen group and 1 event (4%) of femur fracture in the daratumumab group were considered treatment-related TEAE by the investigator. Serious AE occurred in 6 patients (27%) with melflufen, daratumumab, and dexamethasone, and 12 patients (46%) with daratumumab. The most common serious AE (occurring in &ge;4 patients overall) were anemia (melflufen group, 2 patients [9%]; daratumumab group, 3 patients [12%]) and pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]). TEAE leading to treatment discontinuation occurred in 2 patients (9%) in the melflufen group (neutropenia and thrombocytopenia, N=1 each) and 4 patients (15%) in the daratumumab group (anemia, disease progression, hypercalcemia, and renal failure, N=1 each). Overall, 5 patients died on study before the crossover: 2 patients who received melflufen, daratumumab, and dexamethasone (1 due to disease progression and 1 due to unknown reasons, both >30 days after the last dose of study treatment) and 3 patients who received daratumumab (1 due to disease progression and 1 due to unknown reasons, both &le;30 days after the last dose of study treatment and 1 due to an AE [COVID-19 pneumonia], >30 days after the last dose of study treatment). In addition, one patient who crossed over to receive melflufen, daratumumab, and dexamethasone after progression on daratumumab died."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	22 relapsed/refractory multiple myeloma.	Identified from the Human Clinical Data	High Expreesion	Pneumonia	9%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"The safety population included patients who received &ge;1 dose of melflufen, daratumumab, or dexamethasone (melflufen group) and 26 patients who received daratumumab monotherapy. In the safety population, &ge;1 TEAE was reported in 21 patients (96%) with melflufen, daratumumab, and dexamethasone and 22 patients (85%) with daratumumab. Overall, grade &ge;3 TEAE occurred in 18 patients (82%) with melflufen, daratumumab, and dexamethasone and 14 patients (54%) with daratumumab. The most common hematologic grade &ge;3 TEAE were neutropenia (melflufen group, 11 patients [50%]; daratumumab group, 3 patients [12%]), thrombocytopenia (melflufen group, 11 patients [50%]; daratumumab group, 2 patients [8%]), and anemia (melflufen group, 7 patients [32%]; daratumumab group, 5 patients [19%]). The most common non-hematologic grade &ge;3 TEAE were pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]) and femur fracture (melflufen group, 0 patients [0%]; daratumumab group, 2 patients [8%]); of these, 1 event (5%) of pneumonia in the melflufen group and 1 event (4%) of femur fracture in the daratumumab group were considered treatment-related TEAE by the investigator. Serious AE occurred in 6 patients (27%) with melflufen, daratumumab, and dexamethasone, and 12 patients (46%) with daratumumab. The most common serious AE (occurring in &ge;4 patients overall) were anemia (melflufen group, 2 patients [9%]; daratumumab group, 3 patients [12%]) and pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]). TEAE leading to treatment discontinuation occurred in 2 patients (9%) in the melflufen group (neutropenia and thrombocytopenia, N=1 each) and 4 patients (15%) in the daratumumab group (anemia, disease progression, hypercalcemia, and renal failure, N=1 each). Overall, 5 patients died on study before the crossover: 2 patients who received melflufen, daratumumab, and dexamethasone (1 due to disease progression and 1 due to unknown reasons, both >30 days after the last dose of study treatment) and 3 patients who received daratumumab (1 due to disease progression and 1 due to unknown reasons, both &le;30 days after the last dose of study treatment and 1 due to an AE [COVID-19 pneumonia], >30 days after the last dose of study treatment). In addition, one patient who crossed over to receive melflufen, daratumumab, and dexamethasone after progression on daratumumab died."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	22 relapsed/refractory multiple myeloma.	Identified from the Human Clinical Data	High Expreesion	Serious adverse event rate	27%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"The safety population included patients who received &ge;1 dose of melflufen, daratumumab, or dexamethasone (melflufen group) and 26 patients who received daratumumab monotherapy. In the safety population, &ge;1 TEAE was reported in 21 patients (96%) with melflufen, daratumumab, and dexamethasone and 22 patients (85%) with daratumumab. Overall, grade &ge;3 TEAE occurred in 18 patients (82%) with melflufen, daratumumab, and dexamethasone and 14 patients (54%) with daratumumab. The most common hematologic grade &ge;3 TEAE were neutropenia (melflufen group, 11 patients [50%]; daratumumab group, 3 patients [12%]), thrombocytopenia (melflufen group, 11 patients [50%]; daratumumab group, 2 patients [8%]), and anemia (melflufen group, 7 patients [32%]; daratumumab group, 5 patients [19%]). The most common non-hematologic grade &ge;3 TEAE were pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]) and femur fracture (melflufen group, 0 patients [0%]; daratumumab group, 2 patients [8%]); of these, 1 event (5%) of pneumonia in the melflufen group and 1 event (4%) of femur fracture in the daratumumab group were considered treatment-related TEAE by the investigator. Serious AE occurred in 6 patients (27%) with melflufen, daratumumab, and dexamethasone, and 12 patients (46%) with daratumumab. The most common serious AE (occurring in &ge;4 patients overall) were anemia (melflufen group, 2 patients [9%]; daratumumab group, 3 patients [12%]) and pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]). TEAE leading to treatment discontinuation occurred in 2 patients (9%) in the melflufen group (neutropenia and thrombocytopenia, N=1 each) and 4 patients (15%) in the daratumumab group (anemia, disease progression, hypercalcemia, and renal failure, N=1 each). Overall, 5 patients died on study before the crossover: 2 patients who received melflufen, daratumumab, and dexamethasone (1 due to disease progression and 1 due to unknown reasons, both >30 days after the last dose of study treatment) and 3 patients who received daratumumab (1 due to disease progression and 1 due to unknown reasons, both &le;30 days after the last dose of study treatment and 1 due to an AE [COVID-19 pneumonia], >30 days after the last dose of study treatment). In addition, one patient who crossed over to receive melflufen, daratumumab, and dexamethasone after progression on daratumumab died."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	22 relapsed/refractory multiple myeloma.	Identified from the Human Clinical Data	High Expreesion	Anemia	9%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"The safety population included patients who received &ge;1 dose of melflufen, daratumumab, or dexamethasone (melflufen group) and 26 patients who received daratumumab monotherapy. In the safety population, &ge;1 TEAE was reported in 21 patients (96%) with melflufen, daratumumab, and dexamethasone and 22 patients (85%) with daratumumab. Overall, grade &ge;3 TEAE occurred in 18 patients (82%) with melflufen, daratumumab, and dexamethasone and 14 patients (54%) with daratumumab. The most common hematologic grade &ge;3 TEAE were neutropenia (melflufen group, 11 patients [50%]; daratumumab group, 3 patients [12%]), thrombocytopenia (melflufen group, 11 patients [50%]; daratumumab group, 2 patients [8%]), and anemia (melflufen group, 7 patients [32%]; daratumumab group, 5 patients [19%]). The most common non-hematologic grade &ge;3 TEAE were pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]) and femur fracture (melflufen group, 0 patients [0%]; daratumumab group, 2 patients [8%]); of these, 1 event (5%) of pneumonia in the melflufen group and 1 event (4%) of femur fracture in the daratumumab group were considered treatment-related TEAE by the investigator. Serious AE occurred in 6 patients (27%) with melflufen, daratumumab, and dexamethasone, and 12 patients (46%) with daratumumab. The most common serious AE (occurring in &ge;4 patients overall) were anemia (melflufen group, 2 patients [9%]; daratumumab group, 3 patients [12%]) and pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]). TEAE leading to treatment discontinuation occurred in 2 patients (9%) in the melflufen group (neutropenia and thrombocytopenia, N=1 each) and 4 patients (15%) in the daratumumab group (anemia, disease progression, hypercalcemia, and renal failure, N=1 each). Overall, 5 patients died on study before the crossover: 2 patients who received melflufen, daratumumab, and dexamethasone (1 due to disease progression and 1 due to unknown reasons, both >30 days after the last dose of study treatment) and 3 patients who received daratumumab (1 due to disease progression and 1 due to unknown reasons, both &le;30 days after the last dose of study treatment and 1 due to an AE [COVID-19 pneumonia], >30 days after the last dose of study treatment). In addition, one patient who crossed over to receive melflufen, daratumumab, and dexamethasone after progression on daratumumab died."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00275	PDC_00239	Relapsed/Refractory multiple myeloma 	22 relapsed/refractory multiple myeloma.	Identified from the Human Clinical Data	High Expreesion	Pneumonia	9%	%	NCT04649060	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease."	Phase 3	.	.	.	.	.	.	.	.	"The safety population included patients who received &ge;1 dose of melflufen, daratumumab, or dexamethasone (melflufen group) and 26 patients who received daratumumab monotherapy. In the safety population, &ge;1 TEAE was reported in 21 patients (96%) with melflufen, daratumumab, and dexamethasone and 22 patients (85%) with daratumumab. Overall, grade &ge;3 TEAE occurred in 18 patients (82%) with melflufen, daratumumab, and dexamethasone and 14 patients (54%) with daratumumab. The most common hematologic grade &ge;3 TEAE were neutropenia (melflufen group, 11 patients [50%]; daratumumab group, 3 patients [12%]), thrombocytopenia (melflufen group, 11 patients [50%]; daratumumab group, 2 patients [8%]), and anemia (melflufen group, 7 patients [32%]; daratumumab group, 5 patients [19%]). The most common non-hematologic grade &ge;3 TEAE were pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]) and femur fracture (melflufen group, 0 patients [0%]; daratumumab group, 2 patients [8%]); of these, 1 event (5%) of pneumonia in the melflufen group and 1 event (4%) of femur fracture in the daratumumab group were considered treatment-related TEAE by the investigator. Serious AE occurred in 6 patients (27%) with melflufen, daratumumab, and dexamethasone, and 12 patients (46%) with daratumumab. The most common serious AE (occurring in &ge;4 patients overall) were anemia (melflufen group, 2 patients [9%]; daratumumab group, 3 patients [12%]) and pneumonia (melflufen group, 2 patients [9%]; daratumumab group, 2 patients [8%]). TEAE leading to treatment discontinuation occurred in 2 patients (9%) in the melflufen group (neutropenia and thrombocytopenia, N=1 each) and 4 patients (15%) in the daratumumab group (anemia, disease progression, hypercalcemia, and renal failure, N=1 each). Overall, 5 patients died on study before the crossover: 2 patients who received melflufen, daratumumab, and dexamethasone (1 due to disease progression and 1 due to unknown reasons, both >30 days after the last dose of study treatment) and 3 patients who received daratumumab (1 due to disease progression and 1 due to unknown reasons, both &le;30 days after the last dose of study treatment and 1 due to an AE [COVID-19 pneumonia], >30 days after the last dose of study treatment). In addition, one patient who crossed over to receive melflufen, daratumumab, and dexamethasone after progression on daratumumab died."	"Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with 3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received 3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade 3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies."
REF00272	PDC_00009	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	0.058 &plusmn; 0.003 nM	nM	.	.	.	.	Melanoma	DX3-puro/beta6 cell	.	.	48 h	.	WST-1 assay	"Both NH2-PDC-1 and [natCu]PDC-1 exhibited integrin v6-dependent cytotoxicity, only reducing cell viability of the v6-positive cells. For [natCu]PDC-1 high cytotoxicity was observed in DX3puro6 (+) cells (EC50: 0.058 &plusmn; 0.003 nM) with no observable cytotoxic effects in the DX3puro (-) cells, while free MMAE had almost equal cytotoxicity to both DX3puro6 (+) and DX3puro cells (-) (EC50: 0.14-0.15 nM). The pancreatic cells also showed v6-dependent cytotoxicity for [natCu]PDC-1 (EC50: BxPC-3 65.1 &plusmn; 10.6 nM) and required high concentrations of &ge;250 nM for noticeable cytotoxic effects in the minimally integrin v6-expressing MIA PaCa-2 cells. Again, free, non-targeted MMAE exhibited nondiscriminatory cytotoxicity among the pancreatic cells with an effective concentration range of EC50 = 0.16-0.5 nM. Peptides NH2-2 and [natCu]2 were not toxic to any cells."	"Many anticancer drugs exhibit high systemic off-target toxicities causing severe side effects. Peptide-drug conjugates (PDCs) that target tumor-specific receptors such as integrin v&beta;6 are emerging as powerful tools to overcome these challenges. The development of an integrin v&beta;6-selective PDC was achieved by combining the therapeutic efficacy of the cytotoxic drug monomethyl auristatin E with the selectivity of the v&beta;6-binding peptide (v&beta;6-BP) and with the ability of positron emission tomography (PET) imaging by copper-64. The [64Cu]PDC-1 was produced efficiently and in high purity. The PDC exhibited high human serum stability, integrin v&beta;6-selective internalization, cell binding, and cytotoxicity. Integrin v&beta;6-selective tumor accumulation of the [64Cu]PDC-1 was visualized with PET-imaging and corroborated by biodistribution, and [64Cu]PDC-1 showed promising in vivo pharmacokinetics. The [natCu]PDC-1 treatment resulted in prolonged survival of mice bearing v&beta;6 (+) tumors (median survival: 77 days, vs v&beta;6 (-) tumor group 49 days, and all other control groups 37 days)."
REF00272	PDC_00009	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	5 nM	nM	.	.	.	.	Homo sapiens	DX3-puro cell	.	.	48 h	.	WST-1 assay	"Both NH2-PDC-1 and [natCu]PDC-1 exhibited integrin v6-dependent cytotoxicity, only reducing cell viability of the v6-positive cells. For [natCu]PDC-1 high cytotoxicity was observed in DX3puro6 (+) cells (EC50: 0.058 &plusmn; 0.003 nM) with no observable cytotoxic effects in the DX3puro (-) cells, while free MMAE had almost equal cytotoxicity to both DX3puro6 (+) and DX3puro cells (-) (EC50: 0.14-0.15 nM). The pancreatic cells also showed v6-dependent cytotoxicity for [natCu]PDC-1 (EC50: BxPC-3 65.1 &plusmn; 10.6 nM) and required high concentrations of &ge;250 nM for noticeable cytotoxic effects in the minimally integrin v6-expressing MIA PaCa-2 cells. Again, free, non-targeted MMAE exhibited nondiscriminatory cytotoxicity among the pancreatic cells with an effective concentration range of EC50 = 0.16-0.5 nM. Peptides NH2-2 and [natCu]2 were not toxic to any cells."	"Many anticancer drugs exhibit high systemic off-target toxicities causing severe side effects. Peptide-drug conjugates (PDCs) that target tumor-specific receptors such as integrin v&beta;6 are emerging as powerful tools to overcome these challenges. The development of an integrin v&beta;6-selective PDC was achieved by combining the therapeutic efficacy of the cytotoxic drug monomethyl auristatin E with the selectivity of the v&beta;6-binding peptide (v&beta;6-BP) and with the ability of positron emission tomography (PET) imaging by copper-64. The [64Cu]PDC-1 was produced efficiently and in high purity. The PDC exhibited high human serum stability, integrin v&beta;6-selective internalization, cell binding, and cytotoxicity. Integrin v&beta;6-selective tumor accumulation of the [64Cu]PDC-1 was visualized with PET-imaging and corroborated by biodistribution, and [64Cu]PDC-1 showed promising in vivo pharmacokinetics. The [natCu]PDC-1 treatment resulted in prolonged survival of mice bearing v&beta;6 (+) tumors (median survival: 77 days, vs v&beta;6 (-) tumor group 49 days, and all other control groups 37 days)."
REF00272	PDC_00009	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	65.1 &plusmn; 10.6 nM	nM	.	.	.	.	Pancreatic ductal adenocarcinoma	BxPC-3 (+) cells	.	.	48 h	.	WST-1 assay	"Both NH2-PDC-1 and [natCu]PDC-1 exhibited integrin v6-dependent cytotoxicity, only reducing cell viability of the v6-positive cells. For [natCu]PDC-1 high cytotoxicity was observed in DX3puro6 (+) cells (EC50: 0.058 &plusmn; 0.003 nM) with no observable cytotoxic effects in the DX3puro (-) cells, while free MMAE had almost equal cytotoxicity to both DX3puro6 (+) and DX3puro cells (-) (EC50: 0.14-0.15 nM). The pancreatic cells also showed v6-dependent cytotoxicity for [natCu]PDC-1 (EC50: BxPC-3 65.1 &plusmn; 10.6 nM) and required high concentrations of &ge;250 nM for noticeable cytotoxic effects in the minimally integrin v6-expressing MIA PaCa-2 cells. Again, free, non-targeted MMAE exhibited nondiscriminatory cytotoxicity among the pancreatic cells with an effective concentration range of EC50 = 0.16-0.5 nM. Peptides NH2-2 and [natCu]2 were not toxic to any cells."	"Many anticancer drugs exhibit high systemic off-target toxicities causing severe side effects. Peptide-drug conjugates (PDCs) that target tumor-specific receptors such as integrin v&beta;6 are emerging as powerful tools to overcome these challenges. The development of an integrin v&beta;6-selective PDC was achieved by combining the therapeutic efficacy of the cytotoxic drug monomethyl auristatin E with the selectivity of the v&beta;6-binding peptide (v&beta;6-BP) and with the ability of positron emission tomography (PET) imaging by copper-64. The [64Cu]PDC-1 was produced efficiently and in high purity. The PDC exhibited high human serum stability, integrin v&beta;6-selective internalization, cell binding, and cytotoxicity. Integrin v&beta;6-selective tumor accumulation of the [64Cu]PDC-1 was visualized with PET-imaging and corroborated by biodistribution, and [64Cu]PDC-1 showed promising in vivo pharmacokinetics. The [natCu]PDC-1 treatment resulted in prolonged survival of mice bearing v&beta;6 (+) tumors (median survival: 77 days, vs v&beta;6 (-) tumor group 49 days, and all other control groups 37 days)."
REF00272	PDC_00009	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	250 nM	nM	.	.	.	.	Pancreatic ductal adenocarcinoma	MIA PaCa-2 cell	.	.	48 h	.	WST-1 assay	"Both NH2-PDC-1 and [natCu]PDC-1 exhibited integrin v6-dependent cytotoxicity, only reducing cell viability of the v6-positive cells. For [natCu]PDC-1 high cytotoxicity was observed in DX3puro6 (+) cells (EC50: 0.058 &plusmn; 0.003 nM) with no observable cytotoxic effects in the DX3puro (-) cells, while free MMAE had almost equal cytotoxicity to both DX3puro6 (+) and DX3puro cells (-) (EC50: 0.14-0.15 nM). The pancreatic cells also showed v6-dependent cytotoxicity for [natCu]PDC-1 (EC50: BxPC-3 65.1 &plusmn; 10.6 nM) and required high concentrations of &ge;250 nM for noticeable cytotoxic effects in the minimally integrin v6-expressing MIA PaCa-2 cells. Again, free, non-targeted MMAE exhibited nondiscriminatory cytotoxicity among the pancreatic cells with an effective concentration range of EC50 = 0.16-0.5 nM. Peptides NH2-2 and [natCu]2 were not toxic to any cells."	"Many anticancer drugs exhibit high systemic off-target toxicities causing severe side effects. Peptide-drug conjugates (PDCs) that target tumor-specific receptors such as integrin v&beta;6 are emerging as powerful tools to overcome these challenges. The development of an integrin v&beta;6-selective PDC was achieved by combining the therapeutic efficacy of the cytotoxic drug monomethyl auristatin E with the selectivity of the v&beta;6-binding peptide (v&beta;6-BP) and with the ability of positron emission tomography (PET) imaging by copper-64. The [64Cu]PDC-1 was produced efficiently and in high purity. The PDC exhibited high human serum stability, integrin v&beta;6-selective internalization, cell binding, and cytotoxicity. Integrin v&beta;6-selective tumor accumulation of the [64Cu]PDC-1 was visualized with PET-imaging and corroborated by biodistribution, and [64Cu]PDC-1 showed promising in vivo pharmacokinetics. The [natCu]PDC-1 treatment resulted in prolonged survival of mice bearing v&beta;6 (+) tumors (median survival: 77 days, vs v&beta;6 (-) tumor group 49 days, and all other control groups 37 days)."
REF00270	PDC_00322	Lung cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4 &micro;M	&micro;M	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	.	36 h	.	MTT assay	"Doxorubicin (DOX) is one of the most effective anticancer drugs and has been successfully used in clinical practice. However, DOX cannot differentiate between cancer cells and normal cells, which may induce unwanted side effects and severe toxicity. Compared with traditional small-molecule anticancer drugs, the peptide-drug conjugates (PDCs) have enhanced targeting specificity and water solubility. Based on these advantages, to further explore the function of 10a, we designed and prepared a anticancer PDC drug compound RGD-GFLG-DOX containing the tetrapeptide linker Gly-Phe-Leu-Gly, which can be cleaved in presence of cathepsin B, a highly upregulated enzyme in malignant tumors, to release the drug. RGD-GFLG was synthesized as a control. The inhibitory effects of RGD-GFLG-DOX on cancer cell lines were assessed using cytotoxicity assay. Specifically, the effects of RGD-GFLG-DOX were evaluated on integrin v3-positive cancer cell lines, including A549 and U87MG cells, integrin v3-negative cancer cell lines such as HeLa and MCF-7 cells, as well as normal cell lines, namely LO2 and MIHA cells. RGD-GFLG-DOX exhibited a lower cytotoxicity on HeLa, MCF-7, LO2 and MIHA cells, but a stronger cytotoxicity than DOX on A549 and U87MG cells. For comparison, RGD-GFLG demonstrated minimal cytotoxicity. In addition, the cytotoxicity of RGD-GFLG-DOX with various concentrations (0-40 uM) on A549 and U87MG cells was studied. The results showed that the cytotoxicity of RGD-GFLG-DOX on A549 and U87MG cells was dose-dependent. These indicate that RGD-GFLG-DOX has a good specificity and inhibitory activity toward integrin v3-overexpressed A549 and U87MG cells."	"In conclusion, we developed a robust and regioselective rhodium-catalyzed methodology for C(7)-H Trp maleimidation. This reaction served as an efficient tool for peptide/drug modification, ligation, and particularly peptide cyclization, confirming its promising potential in pharmaceutical chemistry and drug synthesis. Notably, this catalytical system is not limited by the Trp position in the peptides. We also demonstrated that tryptophan-substituted maleimide could be used as an effective click functional group to rapidly react with sulfhydryl groups. Moreover, the introduced N-pivaloyl directing group and protecting groups of the peptides could be removed in a single step, providing a more convenient approach compared to the previous methods, which require multi-step removal of the corresponding directing groups and peptide protection groups. Additionally, cyclic peptide 10a exhibited excellent binding affinity to integrin v&beta;3, indicating its good drug-like properties. With rational design, RGD- GFLG -DOX, which is a stapled PDC, displayed higher selectivity, stronger binding affinity and better cell penetrability than the more commonly used DOX. The proposed strategy for rapid preparation of stapled peptides is expected to further improve PDC formulation."
REF00270	PDC_00322	Cervical carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	40 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	36 h	.	MTT assay	"Doxorubicin (DOX) is one of the most effective anticancer drugs and has been successfully used in clinical practice. However, DOX cannot differentiate between cancer cells and normal cells, which may induce unwanted side effects and severe toxicity. Compared with traditional small-molecule anticancer drugs, the peptide-drug conjugates (PDCs) have enhanced targeting specificity and water solubility. Based on these advantages, to further explore the function of 10a, we designed and prepared a anticancer PDC drug compound RGD-GFLG-DOX containing the tetrapeptide linker Gly-Phe-Leu-Gly, which can be cleaved in presence of cathepsin B, a highly upregulated enzyme in malignant tumors, to release the drug. RGD-GFLG was synthesized as a control. The inhibitory effects of RGD-GFLG-DOX on cancer cell lines were assessed using cytotoxicity assay. Specifically, the effects of RGD-GFLG-DOX were evaluated on integrin v3-positive cancer cell lines, including A549 and U87MG cells, integrin v3-negative cancer cell lines such as HeLa and MCF-7 cells, as well as normal cell lines, namely LO2 and MIHA cells. RGD-GFLG-DOX exhibited a lower cytotoxicity on HeLa, MCF-7, LO2 and MIHA cells, but a stronger cytotoxicity than DOX on A549 and U87MG cells. For comparison, RGD-GFLG demonstrated minimal cytotoxicity. In addition, the cytotoxicity of RGD-GFLG-DOX with various concentrations (0-40 uM) on A549 and U87MG cells was studied. The results showed that the cytotoxicity of RGD-GFLG-DOX on A549 and U87MG cells was dose-dependent. These indicate that RGD-GFLG-DOX has a good specificity and inhibitory activity toward integrin v3-overexpressed A549 and U87MG cells."	"In conclusion, we developed a robust and regioselective rhodium-catalyzed methodology for C(7)-H Trp maleimidation. This reaction served as an efficient tool for peptide/drug modification, ligation, and particularly peptide cyclization, confirming its promising potential in pharmaceutical chemistry and drug synthesis. Notably, this catalytical system is not limited by the Trp position in the peptides. We also demonstrated that tryptophan-substituted maleimide could be used as an effective click functional group to rapidly react with sulfhydryl groups. Moreover, the introduced N-pivaloyl directing group and protecting groups of the peptides could be removed in a single step, providing a more convenient approach compared to the previous methods, which require multi-step removal of the corresponding directing groups and peptide protection groups. Additionally, cyclic peptide 10a exhibited excellent binding affinity to integrin v&beta;3, indicating its good drug-like properties. With rational design, RGD- GFLG -DOX, which is a stapled PDC, displayed higher selectivity, stronger binding affinity and better cell penetrability than the more commonly used DOX. The proposed strategy for rapid preparation of stapled peptides is expected to further improve PDC formulation."
REF00270	PDC_00322	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	40 &micro;M	&micro;M	.	.	.	.	Normal	MIHA cell	.	.	36 h	.	MTT assay	"Doxorubicin (DOX) is one of the most effective anticancer drugs and has been successfully used in clinical practice. However, DOX cannot differentiate between cancer cells and normal cells, which may induce unwanted side effects and severe toxicity. Compared with traditional small-molecule anticancer drugs, the peptide-drug conjugates (PDCs) have enhanced targeting specificity and water solubility. Based on these advantages, to further explore the function of 10a, we designed and prepared a anticancer PDC drug compound RGD-GFLG-DOX containing the tetrapeptide linker Gly-Phe-Leu-Gly, which can be cleaved in presence of cathepsin B, a highly upregulated enzyme in malignant tumors, to release the drug. RGD-GFLG was synthesized as a control. The inhibitory effects of RGD-GFLG-DOX on cancer cell lines were assessed using cytotoxicity assay. Specifically, the effects of RGD-GFLG-DOX were evaluated on integrin v3-positive cancer cell lines, including A549 and U87MG cells, integrin v3-negative cancer cell lines such as HeLa and MCF-7 cells, as well as normal cell lines, namely LO2 and MIHA cells. RGD-GFLG-DOX exhibited a lower cytotoxicity on HeLa, MCF-7, LO2 and MIHA cells, but a stronger cytotoxicity than DOX on A549 and U87MG cells. For comparison, RGD-GFLG demonstrated minimal cytotoxicity. In addition, the cytotoxicity of RGD-GFLG-DOX with various concentrations (0-40 uM) on A549 and U87MG cells was studied. The results showed that the cytotoxicity of RGD-GFLG-DOX on A549 and U87MG cells was dose-dependent. These indicate that RGD-GFLG-DOX has a good specificity and inhibitory activity toward integrin v3-overexpressed A549 and U87MG cells."	"In conclusion, we developed a robust and regioselective rhodium-catalyzed methodology for C(7)-H Trp maleimidation. This reaction served as an efficient tool for peptide/drug modification, ligation, and particularly peptide cyclization, confirming its promising potential in pharmaceutical chemistry and drug synthesis. Notably, this catalytical system is not limited by the Trp position in the peptides. We also demonstrated that tryptophan-substituted maleimide could be used as an effective click functional group to rapidly react with sulfhydryl groups. Moreover, the introduced N-pivaloyl directing group and protecting groups of the peptides could be removed in a single step, providing a more convenient approach compared to the previous methods, which require multi-step removal of the corresponding directing groups and peptide protection groups. Additionally, cyclic peptide 10a exhibited excellent binding affinity to integrin v&beta;3, indicating its good drug-like properties. With rational design, RGD- GFLG -DOX, which is a stapled PDC, displayed higher selectivity, stronger binding affinity and better cell penetrability than the more commonly used DOX. The proposed strategy for rapid preparation of stapled peptides is expected to further improve PDC formulation."
REF00270	PDC_00322	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U-87MG cell	.	.	36 h	.	MTT assay	"Doxorubicin (DOX) is one of the most effective anticancer drugs and has been successfully used in clinical practice. However, DOX cannot differentiate between cancer cells and normal cells, which may induce unwanted side effects and severe toxicity. Compared with traditional small-molecule anticancer drugs, the peptide-drug conjugates (PDCs) have enhanced targeting specificity and water solubility. Based on these advantages, to further explore the function of 10a, we designed and prepared a anticancer PDC drug compound RGD-GFLG-DOX containing the tetrapeptide linker Gly-Phe-Leu-Gly, which can be cleaved in presence of cathepsin B, a highly upregulated enzyme in malignant tumors, to release the drug. RGD-GFLG was synthesized as a control. The inhibitory effects of RGD-GFLG-DOX on cancer cell lines were assessed using cytotoxicity assay. Specifically, the effects of RGD-GFLG-DOX were evaluated on integrin v3-positive cancer cell lines, including A549 and U87MG cells, integrin v3-negative cancer cell lines such as HeLa and MCF-7 cells, as well as normal cell lines, namely LO2 and MIHA cells. RGD-GFLG-DOX exhibited a lower cytotoxicity on HeLa, MCF-7, LO2 and MIHA cells, but a stronger cytotoxicity than DOX on A549 and U87MG cells. For comparison, RGD-GFLG demonstrated minimal cytotoxicity. In addition, the cytotoxicity of RGD-GFLG-DOX with various concentrations (0-40 uM) on A549 and U87MG cells was studied. The results showed that the cytotoxicity of RGD-GFLG-DOX on A549 and U87MG cells was dose-dependent. These indicate that RGD-GFLG-DOX has a good specificity and inhibitory activity toward integrin v3-overexpressed A549 and U87MG cells."	"In conclusion, we developed a robust and regioselective rhodium-catalyzed methodology for C(7)-H Trp maleimidation. This reaction served as an efficient tool for peptide/drug modification, ligation, and particularly peptide cyclization, confirming its promising potential in pharmaceutical chemistry and drug synthesis. Notably, this catalytical system is not limited by the Trp position in the peptides. We also demonstrated that tryptophan-substituted maleimide could be used as an effective click functional group to rapidly react with sulfhydryl groups. Moreover, the introduced N-pivaloyl directing group and protecting groups of the peptides could be removed in a single step, providing a more convenient approach compared to the previous methods, which require multi-step removal of the corresponding directing groups and peptide protection groups. Additionally, cyclic peptide 10a exhibited excellent binding affinity to integrin v&beta;3, indicating its good drug-like properties. With rational design, RGD- GFLG -DOX, which is a stapled PDC, displayed higher selectivity, stronger binding affinity and better cell penetrability than the more commonly used DOX. The proposed strategy for rapid preparation of stapled peptides is expected to further improve PDC formulation."
REF00270	PDC_00322	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	40 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	36 h	.	MTT assay	"Doxorubicin (DOX) is one of the most effective anticancer drugs and has been successfully used in clinical practice. However, DOX cannot differentiate between cancer cells and normal cells, which may induce unwanted side effects and severe toxicity. Compared with traditional small-molecule anticancer drugs, the peptide-drug conjugates (PDCs) have enhanced targeting specificity and water solubility. Based on these advantages, to further explore the function of 10a, we designed and prepared a anticancer PDC drug compound RGD-GFLG-DOX containing the tetrapeptide linker Gly-Phe-Leu-Gly, which can be cleaved in presence of cathepsin B, a highly upregulated enzyme in malignant tumors, to release the drug. RGD-GFLG was synthesized as a control. The inhibitory effects of RGD-GFLG-DOX on cancer cell lines were assessed using cytotoxicity assay. Specifically, the effects of RGD-GFLG-DOX were evaluated on integrin v3-positive cancer cell lines, including A549 and U87MG cells, integrin v3-negative cancer cell lines such as HeLa and MCF-7 cells, as well as normal cell lines, namely LO2 and MIHA cells. RGD-GFLG-DOX exhibited a lower cytotoxicity on HeLa, MCF-7, LO2 and MIHA cells, but a stronger cytotoxicity than DOX on A549 and U87MG cells. For comparison, RGD-GFLG demonstrated minimal cytotoxicity. In addition, the cytotoxicity of RGD-GFLG-DOX with various concentrations (0-40 uM) on A549 and U87MG cells was studied. The results showed that the cytotoxicity of RGD-GFLG-DOX on A549 and U87MG cells was dose-dependent. These indicate that RGD-GFLG-DOX has a good specificity and inhibitory activity toward integrin v3-overexpressed A549 and U87MG cells."	"In conclusion, we developed a robust and regioselective rhodium-catalyzed methodology for C(7)-H Trp maleimidation. This reaction served as an efficient tool for peptide/drug modification, ligation, and particularly peptide cyclization, confirming its promising potential in pharmaceutical chemistry and drug synthesis. Notably, this catalytical system is not limited by the Trp position in the peptides. We also demonstrated that tryptophan-substituted maleimide could be used as an effective click functional group to rapidly react with sulfhydryl groups. Moreover, the introduced N-pivaloyl directing group and protecting groups of the peptides could be removed in a single step, providing a more convenient approach compared to the previous methods, which require multi-step removal of the corresponding directing groups and peptide protection groups. Additionally, cyclic peptide 10a exhibited excellent binding affinity to integrin v&beta;3, indicating its good drug-like properties. With rational design, RGD- GFLG -DOX, which is a stapled PDC, displayed higher selectivity, stronger binding affinity and better cell penetrability than the more commonly used DOX. The proposed strategy for rapid preparation of stapled peptides is expected to further improve PDC formulation."
REF00270	PDC_00322	Liver cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	40 &micro;M	&micro;M	.	.	.	.	Amelanotic melanoma	LO #2 cell	.	.	36 h	.	MTT assay	"Doxorubicin (DOX) is one of the most effective anticancer drugs and has been successfully used in clinical practice. However, DOX cannot differentiate between cancer cells and normal cells, which may induce unwanted side effects and severe toxicity. Compared with traditional small-molecule anticancer drugs, the peptide-drug conjugates (PDCs) have enhanced targeting specificity and water solubility. Based on these advantages, to further explore the function of 10a, we designed and prepared a anticancer PDC drug compound RGD-GFLG-DOX containing the tetrapeptide linker Gly-Phe-Leu-Gly, which can be cleaved in presence of cathepsin B, a highly upregulated enzyme in malignant tumors, to release the drug. RGD-GFLG was synthesized as a control. The inhibitory effects of RGD-GFLG-DOX on cancer cell lines were assessed using cytotoxicity assay. Specifically, the effects of RGD-GFLG-DOX were evaluated on integrin v3-positive cancer cell lines, including A549 and U87MG cells, integrin v3-negative cancer cell lines such as HeLa and MCF-7 cells, as well as normal cell lines, namely LO2 and MIHA cells. RGD-GFLG-DOX exhibited a lower cytotoxicity on HeLa, MCF-7, LO2 and MIHA cells, but a stronger cytotoxicity than DOX on A549 and U87MG cells. For comparison, RGD-GFLG demonstrated minimal cytotoxicity. In addition, the cytotoxicity of RGD-GFLG-DOX with various concentrations (0-40 uM) on A549 and U87MG cells was studied. The results showed that the cytotoxicity of RGD-GFLG-DOX on A549 and U87MG cells was dose-dependent. These indicate that RGD-GFLG-DOX has a good specificity and inhibitory activity toward integrin v3-overexpressed A549 and U87MG cells."	"In conclusion, we developed a robust and regioselective rhodium-catalyzed methodology for C(7)-H Trp maleimidation. This reaction served as an efficient tool for peptide/drug modification, ligation, and particularly peptide cyclization, confirming its promising potential in pharmaceutical chemistry and drug synthesis. Notably, this catalytical system is not limited by the Trp position in the peptides. We also demonstrated that tryptophan-substituted maleimide could be used as an effective click functional group to rapidly react with sulfhydryl groups. Moreover, the introduced N-pivaloyl directing group and protecting groups of the peptides could be removed in a single step, providing a more convenient approach compared to the previous methods, which require multi-step removal of the corresponding directing groups and peptide protection groups. Additionally, cyclic peptide 10a exhibited excellent binding affinity to integrin v&beta;3, indicating its good drug-like properties. With rational design, RGD- GFLG -DOX, which is a stapled PDC, displayed higher selectivity, stronger binding affinity and better cell penetrability than the more commonly used DOX. The proposed strategy for rapid preparation of stapled peptides is expected to further improve PDC formulation."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	4.4 months	months	.	.	.	96 relapsed/refractory multiple myeloma patients aged <65 years.	.	.	.	.	.	.	.	"In this updated survival analysis, median OS (95% CI) was 20.2 months (15.8-24.3) with melflufen and 24.0 months (19.1-28.7) with pomalidomide (HR, 1.14 [95% CI, 0.91-1.43]; P =.24), with a median follow-up time of 31.8 months and 29.8 months, respectively. Because of imbalance in the number of patients who were randomized but not treated, survival was also evaluated in the safety population: median OS (95% CI) was 21.3 months (16.6-24.8) with melflufen and 24.0 months (19.8-28.7) with pomalidomide (HR, 1.12 [95% CI, 0.89-1.42]; P =.33), with the curves overlapping until 10 months after randomization. Sensitivity analyses revealed that the uneven distribution of randomized but not treated patients impacted OS, but not PFS. Although a similar number of patients received subsequent therapy after OCEAN (melflufen group, 169/246 [69%] patients; pomalidomide group, 164/249 [66%] patients), the type of subsequent therapy and timing of subsequent therapy initiation differed between treatment groups."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	16.2 months	months	.	.	.	96 relapsed/refractory multiple myeloma patients aged <65 years.	.	.	.	.	.	.	.	"In this updated survival analysis, median OS (95% CI) was 20.2 months (15.8-24.3) with melflufen and 24.0 months (19.1-28.7) with pomalidomide (HR, 1.14 [95% CI, 0.91-1.43]; P =.24), with a median follow-up time of 31.8 months and 29.8 months, respectively. Because of imbalance in the number of patients who were randomized but not treated, survival was also evaluated in the safety population: median OS (95% CI) was 21.3 months (16.6-24.8) with melflufen and 24.0 months (19.8-28.7) with pomalidomide (HR, 1.12 [95% CI, 0.89-1.42]; P =.33), with the curves overlapping until 10 months after randomization. Sensitivity analyses revealed that the uneven distribution of randomized but not treated patients impacted OS, but not PFS. Although a similar number of patients received subsequent therapy after OCEAN (melflufen group, 169/246 [69%] patients; pomalidomide group, 164/249 [66%] patients), the type of subsequent therapy and timing of subsequent therapy initiation differed between treatment groups."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Hazard ratio	168%	%	.	.	.	96 relapsed/refractory multiple myeloma patients aged <65 years.	.	.	.	.	.	.	.	"In this updated survival analysis, median OS (95% CI) was 20.2 months (15.8-24.3) with melflufen and 24.0 months (19.1-28.7) with pomalidomide (HR, 1.14 [95% CI, 0.91-1.43]; P =.24), with a median follow-up time of 31.8 months and 29.8 months, respectively. Because of imbalance in the number of patients who were randomized but not treated, survival was also evaluated in the safety population: median OS (95% CI) was 21.3 months (16.6-24.8) with melflufen and 24.0 months (19.8-28.7) with pomalidomide (HR, 1.12 [95% CI, 0.89-1.42]; P =.33), with the curves overlapping until 10 months after randomization. Sensitivity analyses revealed that the uneven distribution of randomized but not treated patients impacted OS, but not PFS. Although a similar number of patients received subsequent therapy after OCEAN (melflufen group, 169/246 [69%] patients; pomalidomide group, 164/249 [66%] patients), the type of subsequent therapy and timing of subsequent therapy initiation differed between treatment groups."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	7.2 months	months	.	.	.	113 relapsed/refractory multiple myeloma patients aged 65-74 years.	.	.	.	.	.	.	.	"In this updated survival analysis, median OS (95% CI) was 20.2 months (15.8-24.3) with melflufen and 24.0 months (19.1-28.7) with pomalidomide (HR, 1.14 [95% CI, 0.91-1.43]; P =.24), with a median follow-up time of 31.8 months and 29.8 months, respectively. Because of imbalance in the number of patients who were randomized but not treated, survival was also evaluated in the safety population: median OS (95% CI) was 21.3 months (16.6-24.8) with melflufen and 24.0 months (19.8-28.7) with pomalidomide (HR, 1.12 [95% CI, 0.89-1.42]; P =.33), with the curves overlapping until 10 months after randomization. Sensitivity analyses revealed that the uneven distribution of randomized but not treated patients impacted OS, but not PFS. Although a similar number of patients received subsequent therapy after OCEAN (melflufen group, 169/246 [69%] patients; pomalidomide group, 164/249 [66%] patients), the type of subsequent therapy and timing of subsequent therapy initiation differed between treatment groups."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	20.5 months	months	.	.	.	113 relapsed/refractory multiple myeloma patients aged 65-74 years.	.	.	.	.	.	.	.	"In this updated survival analysis, median OS (95% CI) was 20.2 months (15.8-24.3) with melflufen and 24.0 months (19.1-28.7) with pomalidomide (HR, 1.14 [95% CI, 0.91-1.43]; P =.24), with a median follow-up time of 31.8 months and 29.8 months, respectively. Because of imbalance in the number of patients who were randomized but not treated, survival was also evaluated in the safety population: median OS (95% CI) was 21.3 months (16.6-24.8) with melflufen and 24.0 months (19.8-28.7) with pomalidomide (HR, 1.12 [95% CI, 0.89-1.42]; P =.33), with the curves overlapping until 10 months after randomization. Sensitivity analyses revealed that the uneven distribution of randomized but not treated patients impacted OS, but not PFS. Although a similar number of patients received subsequent therapy after OCEAN (melflufen group, 169/246 [69%] patients; pomalidomide group, 164/249 [66%] patients), the type of subsequent therapy and timing of subsequent therapy initiation differed between treatment groups."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Hazard ratio	103%	%	.	.	.	113 relapsed/refractory multiple myeloma patients aged 65-74 years.	.	.	.	.	.	.	.	"In this updated survival analysis, median OS (95% CI) was 20.2 months (15.8-24.3) with melflufen and 24.0 months (19.1-28.7) with pomalidomide (HR, 1.14 [95% CI, 0.91-1.43]; P =.24), with a median follow-up time of 31.8 months and 29.8 months, respectively. Because of imbalance in the number of patients who were randomized but not treated, survival was also evaluated in the safety population: median OS (95% CI) was 21.3 months (16.6-24.8) with melflufen and 24.0 months (19.8-28.7) with pomalidomide (HR, 1.12 [95% CI, 0.89-1.42]; P =.33), with the curves overlapping until 10 months after randomization. Sensitivity analyses revealed that the uneven distribution of randomized but not treated patients impacted OS, but not PFS. Although a similar number of patients received subsequent therapy after OCEAN (melflufen group, 169/246 [69%] patients; pomalidomide group, 164/249 [66%] patients), the type of subsequent therapy and timing of subsequent therapy initiation differed between treatment groups."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	9.3 months	months	.	.	.	37 relapsed/refractory multiple myeloma patients aged 75 years.	.	.	.	.	.	.	.	"In this updated survival analysis, median OS (95% CI) was 20.2 months (15.8-24.3) with melflufen and 24.0 months (19.1-28.7) with pomalidomide (HR, 1.14 [95% CI, 0.91-1.43]; P =.24), with a median follow-up time of 31.8 months and 29.8 months, respectively. Because of imbalance in the number of patients who were randomized but not treated, survival was also evaluated in the safety population: median OS (95% CI) was 21.3 months (16.6-24.8) with melflufen and 24.0 months (19.8-28.7) with pomalidomide (HR, 1.12 [95% CI, 0.89-1.42]; P =.33), with the curves overlapping until 10 months after randomization. Sensitivity analyses revealed that the uneven distribution of randomized but not treated patients impacted OS, but not PFS. Although a similar number of patients received subsequent therapy after OCEAN (melflufen group, 169/246 [69%] patients; pomalidomide group, 164/249 [66%] patients), the type of subsequent therapy and timing of subsequent therapy initiation differed between treatment groups."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	26.5 months	months	.	.	.	37 relapsed/refractory multiple myeloma patients aged 75 years.	.	.	.	.	.	.	.	"In this updated survival analysis, median OS (95% CI) was 20.2 months (15.8-24.3) with melflufen and 24.0 months (19.1-28.7) with pomalidomide (HR, 1.14 [95% CI, 0.91-1.43]; P =.24), with a median follow-up time of 31.8 months and 29.8 months, respectively. Because of imbalance in the number of patients who were randomized but not treated, survival was also evaluated in the safety population: median OS (95% CI) was 21.3 months (16.6-24.8) with melflufen and 24.0 months (19.8-28.7) with pomalidomide (HR, 1.12 [95% CI, 0.89-1.42]; P =.33), with the curves overlapping until 10 months after randomization. Sensitivity analyses revealed that the uneven distribution of randomized but not treated patients impacted OS, but not PFS. Although a similar number of patients received subsequent therapy after OCEAN (melflufen group, 169/246 [69%] patients; pomalidomide group, 164/249 [66%] patients), the type of subsequent therapy and timing of subsequent therapy initiation differed between treatment groups."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Hazard ratio	62%	%	.	.	.	37 relapsed/refractory multiple myeloma patients aged 75 years.	.	.	.	.	.	.	.	"In this updated survival analysis, median OS (95% CI) was 20.2 months (15.8-24.3) with melflufen and 24.0 months (19.1-28.7) with pomalidomide (HR, 1.14 [95% CI, 0.91-1.43]; P =.24), with a median follow-up time of 31.8 months and 29.8 months, respectively. Because of imbalance in the number of patients who were randomized but not treated, survival was also evaluated in the safety population: median OS (95% CI) was 21.3 months (16.6-24.8) with melflufen and 24.0 months (19.8-28.7) with pomalidomide (HR, 1.12 [95% CI, 0.89-1.42]; P =.33), with the curves overlapping until 10 months after randomization. Sensitivity analyses revealed that the uneven distribution of randomized but not treated patients impacted OS, but not PFS. Although a similar number of patients received subsequent therapy after OCEAN (melflufen group, 169/246 [69%] patients; pomalidomide group, 164/249 [66%] patients), the type of subsequent therapy and timing of subsequent therapy initiation differed between treatment groups."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	99%	%	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	88%	%	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	44%	%	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	11%	%	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	48%	%	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	58%	%	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	23%	%	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	70%	%	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Hemorrhage	3%	%	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia concurrent with hemorrhage	1%	%	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Neutropenia	66%	%	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Infection	15%	%	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Neutropenia concurrent with grade 3/4 infection	2%	%	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median duration of treatment	35.1 weeks	weeks	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median time to dose reduction	21.6 weeks	weeks	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median time to grade 3/4 thrombocytopenia	11.2 weeks	weeks	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median time to grade 3/4 neutropenia	4.8 weeks	weeks	.	.	.	145 patients who has relapsed/refractory multiple myeloma with no previous ASCT or TTP >36 month Post-ASCTa.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	99%	%	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	92%	%	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	38%	%	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	13%	%	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	45%	%	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	63%	%	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	31%	%	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	86%	%	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Hemorrhage	1%	%	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia concurrent with hemorrhage	0%	%	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Neutropenia	62%	%	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Infection	11%	%	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Neutropenia concurrent with grade 3/4 infection	4%	%	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median duration of treatment	15.1 weeks	weeks	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median time to dose reduction	10.1 weeks	weeks	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median time to grade 3/4 thrombocytopenia	4.1 weeks	weeks	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00269	PDC_00239	Relapsed/Refractory multiple myeloma 	.	Identified from the Human Clinical Data	High Expreesion	Median time to grade 3/4 neutropenia	2.1 weeks	weeks	.	.	.	101 relapsed/refractory multiple myeloma patients with TTP <36 month Post-ASCTb.	.	.	.	.	.	.	.	"Given the prognostic importance of TTP <36 months post-ASCT in OCEAN, we evaluated this prognostic factor in a post hoc analysis from the HORIZON study. Among 110 patients with triple-class refractory disease who had received &ge;3 prior lines of therapy, 77 (70%) had received a previous ASCT and 58 (53%) had TTP <36 months post-ASCT (Suppl. Table S3). In patients with a TTP >36 months post-ASCT or no ASCT versus patients with a TTP <36 months post-ASCT, ORR was higher (29% vs 22%; Suppl. Table S4) and median DOR (7.6 months vs 3.9 months) and median PFS (4.2 months vs 3.4 months) were longer. Since pomalidomide and lenalidomide both belong to the immunomodulatory drugs, we analyzed if the duration of previous treatment with lenalidomide could have impacted the results. The median duration of lenalidomide was 14.4 months in patients with ASCT and TTP < 36 months, 38.3 months in patients with ASCT and TTP > 36 months, and 14.6 months in patients with no previous ASCT. However, the median PFS for patients treated with pomalidomide did not differ substantially between these groups of patients. The safety profile of melflufen and dexamethasone was generally consistent between patients with a TTP >36 months post-ASCT or no ASCT and patients with a TTP <36 months post-ASCT. In OCEAN among the melflufen group, the frequency of grade 3/4 TEAEs (88% and 92%), serious TEAEs (44% and 38%), and fatal adverse events (AEs; 11% and 13%) was similar in patients with a TTP >36 months post-ASCT or no ASCT and patients with TTP <36 months. However, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of TEAEs leading to treatment discontinuation (23% and 31%), the longer median duration of study treatment (35.1 weeks vs 15.1 weeks), and longer median time to experiencing grade 3/4 thrombocytopenia (11.2 weeks vs 4.1 weeks) and grade 3/4 neutropenia (4.8 weeks vs 2.1 weeks) than patients with a TTP <36 months post-ASCT. In HORIZON, patients with a TTP >36 months post-ASCT or no ASCT had lower rates of grade 3/4 TEAEs (88% and 98%), but higher rates of serious TEAEs (64% and 53%) and similar rates of TEAEs leading to treatment discontinuation (29% and 33%) than patients with a TTP <36 months post-ASCT."	"In summary, the interpretation of the results from the OCEAN study were impacted by the heterogeneity of the population, with age and previous success of ASCT therapy identified as prognostic factors with study therapies. The safety profile of melflufen and dexamethasone is primarily characterized by hematologic AEs that are clinically manageable. Observed infection rates, which included COVID-19, were generally low. Taken together, these data support the use of melflufen and dexamethasone in patients who have not received a previous ASCT or who underwent a successful ASCT (ie, TTP >36 months post-ASCT). In addition, the favorable efficacy profile and convenience of monthly outpatient infusions, especially for patients without access to other therapeutics such as CAR T-cell therapy or bispecific antibodies, bode well for this combination translating successfully into real-world practice."
REF00268	PDC_00303	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.3 &plusmn; 0.2&micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"Several PDCs have been prepared with peptide 18-4 and doxorubicin (Dox) using different linker chemistries such as ester, amide, succinimidyl thioether, or acyl hydrazone. In vitro results showed that these PDCs were highly specific toward breast cancer cells. PDCs displayed similar toxicity as free Dox toward the breast cancer cells and several-fold (7-40 times) less toxicity toward the non-cancerous cells such as MCF-10A and human umbilical vein endothelial cells (HUVECs). A peptide 18-4-Dox conjugate with amide/succinimidyl thioether linkage showed high selective toxicity toward triple negative breast cancer (TNBC) cell lines, i.e., MDA-MB-231 cells (IC50 1.3 &plusmn; 0.2 uM) and MDA-MB-468 cells (IC50 4.7 &plusmn; 0.3 uM) compared to the normal breast MCF10A cells (IC50 38.6 &plusmn; 1.1 uM). The linkage between the drug and the peptide was stable as the degradation half-life of peptide 18-4-Dox conjugate in the presence of human serum was found to be &tilde;18 h. Herein, we describe the first in vivo evidence for improved efficacy of this PDC targeting K1 receptor in an orthotopic TNBC mouse model. We also show a higher accumulation of PDC in TNBC tumors in mice, in accord with K1 overexpression in tumor over non-tumor tissues in MDA-MB-231 xenografted mice."	"We engineered peptides that bind to cell-surface K1 and are internalized by breast cancer cells via cell-surface K1 receptor-mediated endocytosis. Peptide 18-4 (WxEAAYQrFL), with two D-amino acids, is a second-generation breast cancer cell-targeting peptide that is proteolytically stable (100% intact up to 24 h when incubated with human serum or liver homogenate from mice) and has shown high specific uptake by breast cancer cells and minimal/no binding to non-cancerous cells. Affinity purification of breast cancer cell lysates using the immobilized peptide, followed by liquid chromatography-tandem mass spectrometry and proteomics were used to identify K1 as the novel target for peptide 18-4 in cancer cells. Further, we showed that the uptake of the peptide by the cancer cells is dependent on K1 expression."
REF00268	PDC_00303	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.7 &plusmn; 0.3&micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	.	.	.	"Several PDCs have been prepared with peptide 18-4 and doxorubicin (Dox) using different linker chemistries such as ester, amide, succinimidyl thioether, or acyl hydrazone. In vitro results showed that these PDCs were highly specific toward breast cancer cells. PDCs displayed similar toxicity as free Dox toward the breast cancer cells and several-fold (7-40 times) less toxicity toward the non-cancerous cells such as MCF-10A and human umbilical vein endothelial cells (HUVECs). A peptide 18-4-Dox conjugate with amide/succinimidyl thioether linkage showed high selective toxicity toward triple negative breast cancer (TNBC) cell lines, i.e., MDA-MB-231 cells (IC50 1.3 &plusmn; 0.2 uM) and MDA-MB-468 cells (IC50 4.7 &plusmn; 0.3 uM) compared to the normal breast MCF10A cells (IC50 38.6 &plusmn; 1.1 uM). The linkage between the drug and the peptide was stable as the degradation half-life of peptide 18-4-Dox conjugate in the presence of human serum was found to be &tilde;18 h. Herein, we describe the first in vivo evidence for improved efficacy of this PDC targeting K1 receptor in an orthotopic TNBC mouse model. We also show a higher accumulation of PDC in TNBC tumors in mice, in accord with K1 overexpression in tumor over non-tumor tissues in MDA-MB-231 xenografted mice."	"We engineered peptides that bind to cell-surface K1 and are internalized by breast cancer cells via cell-surface K1 receptor-mediated endocytosis. Peptide 18-4 (WxEAAYQrFL), with two D-amino acids, is a second-generation breast cancer cell-targeting peptide that is proteolytically stable (100% intact up to 24 h when incubated with human serum or liver homogenate from mice) and has shown high specific uptake by breast cancer cells and minimal/no binding to non-cancerous cells. Affinity purification of breast cancer cell lysates using the immobilized peptide, followed by liquid chromatography-tandem mass spectrometry and proteomics were used to identify K1 as the novel target for peptide 18-4 in cancer cells. Further, we showed that the uptake of the peptide by the cancer cells is dependent on K1 expression."
REF00268	PDC_00303	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	38.6 &plusmn; 1.1&micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	.	.	.	"Several PDCs have been prepared with peptide 18-4 and doxorubicin (Dox) using different linker chemistries such as ester, amide, succinimidyl thioether, or acyl hydrazone. In vitro results showed that these PDCs were highly specific toward breast cancer cells. PDCs displayed similar toxicity as free Dox toward the breast cancer cells and several-fold (7-40 times) less toxicity toward the non-cancerous cells such as MCF-10A and human umbilical vein endothelial cells (HUVECs). A peptide 18-4-Dox conjugate with amide/succinimidyl thioether linkage showed high selective toxicity toward triple negative breast cancer (TNBC) cell lines, i.e., MDA-MB-231 cells (IC50 1.3 &plusmn; 0.2 uM) and MDA-MB-468 cells (IC50 4.7 &plusmn; 0.3 uM) compared to the normal breast MCF10A cells (IC50 38.6 &plusmn; 1.1 uM). The linkage between the drug and the peptide was stable as the degradation half-life of peptide 18-4-Dox conjugate in the presence of human serum was found to be &tilde;18 h. Herein, we describe the first in vivo evidence for improved efficacy of this PDC targeting K1 receptor in an orthotopic TNBC mouse model. We also show a higher accumulation of PDC in TNBC tumors in mice, in accord with K1 overexpression in tumor over non-tumor tissues in MDA-MB-231 xenografted mice."	"We engineered peptides that bind to cell-surface K1 and are internalized by breast cancer cells via cell-surface K1 receptor-mediated endocytosis. Peptide 18-4 (WxEAAYQrFL), with two D-amino acids, is a second-generation breast cancer cell-targeting peptide that is proteolytically stable (100% intact up to 24 h when incubated with human serum or liver homogenate from mice) and has shown high specific uptake by breast cancer cells and minimal/no binding to non-cancerous cells. Affinity purification of breast cancer cell lysates using the immobilized peptide, followed by liquid chromatography-tandem mass spectrometry and proteomics were used to identify K1 as the novel target for peptide 18-4 in cancer cells. Further, we showed that the uptake of the peptide by the cancer cells is dependent on K1 expression."
REF00266	PDC_00081	Malignant glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	25.82 &plusmn; 0.31 nM	nM	.	.	.	.	Glioblastoma	U-87MG cell	.	.	24 h	.	MTT assay	"Furthermore, it was also observed that PDC shows time-dependent cytotoxicity against U87MG cells, as at 12 h drug treatment. PDC shows a slightly lower inhibitory effect on cell survival (EC50 = 25.82 &plusmn; 0.31 nM) than PTX alone (EC50 = 12.25 &plusmn; 0.13 nM), and CPP-SA alone shows higher EC50 = 54.37 &plusmn; 0.24 in U87MG cells. Besides this, it was previously observed that CPP-treated healthy VERO cells showed 88.05 &plusmn; 0.86% viable cells even using 10 uM concentration, indicating the specificity of CPP for glioblastoma cells. However, at 24 h incubation period, our PDC shows a significantly enhanced cell survival inhibitory effect with EC50 = 8.32 &plusmn; 0.09 nM, suggesting the delayed effect of PDC because of the time required for the intracellular pH to cause maximal cleavage of PTX from the PDC. Moreover, it also shows that CPP-SA has a lower cytotoxicity effect on glioblastoma cells compared with PTX alone and PDC, indicating its specificity as a carrier and selectivity for integrin receptors overexpressed on the cell surface. Additionally, we have also studied the potential of our novel-designed PDC to internalize into PTX-resistant glioblastoma (U87MG-PR) cells to show cytotoxic activity upon intracellular cleavage of PTX from CPP. The data presented in Figure 3b reveal approximately 15% viability increases in U87MG-PR cells compared with parent U87MG cells. It can be seen in the inset in Figure 3b that PTX alone (EC50 = 41.3 &plusmn; 1.5 nM) showed significantly 2-fold reduced cytotoxic activity in U87MG-PR cells in comparison with our novel-designed PDC having EC50 = 20.55 &plusmn; 1.02 nM. It was also observed in Figure 3b that at lower concentrations (0-10 nM) the viable cell count was &tilde;75%; however, it significantly decreased to &tilde;20% viability with an increase in concentration (40 nM) of the test samples, highlighting the dose-dependent cytotoxicity behavior of PDC in a 24 h incubation period."	"A highly sensitive, nontoxic, hydrophilic cell-penetrating peptide (CPP = c[RGDKLAK]) was selected for the construction of an effective peptide-drug conjugate (PDC). A hydrophobic drug paclitaxel (PTX) was successfully conjugated with CPP via ester linkage with succinic acid (SA) as a pH-cleavable linker moiety. The characterization techniques employed in this study indicate the >95% purity of the resulting PDC (CPP-SA-PTX). The in vitro studies show that our proposed PDC exhibits enhanced stability (&tilde;90%) and cytotoxicity (EC50 = 8.32 &plusmn; 0.09 nM). Besides the excellent solubility of PDC in water, the PTX effect on positive &beta;-tubulin-III indicates that the drug releases retained pharmacological properties. Additionally, in vivo, therapeutic-dose treatment reveals the prominent tumor-growth inhibitory effects (2.82-3.24-fold) of PDC in tumor mice models. Subsequently, these observations confirmed that our novel-designed PDC (CPP-SA-PTX) adduct may serve as a promising therapeutic agent to treat glioblastoma."
REF00266	PDC_00081	Malignant glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Effective Concentration (EC50)	20.55 &plusmn; 1.02 nM	nM	.	.	.	.	Glioblastoma	U87MG-PR cell	.	.	24 h	.	MTT assay	"Furthermore, it was also observed that PDC shows time-dependent cytotoxicity against U87MG cells, as at 12 h drug treatment. PDC shows a slightly lower inhibitory effect on cell survival (EC50 = 25.82 &plusmn; 0.31 nM) than PTX alone (EC50 = 12.25 &plusmn; 0.13 nM), and CPP-SA alone shows higher EC50 = 54.37 &plusmn; 0.24 in U87MG cells. Besides this, it was previously observed that CPP-treated healthy VERO cells showed 88.05 &plusmn; 0.86% viable cells even using 10 uM concentration, indicating the specificity of CPP for glioblastoma cells. However, at 24 h incubation period, our PDC shows a significantly enhanced cell survival inhibitory effect with EC50 = 8.32 &plusmn; 0.09 nM, suggesting the delayed effect of PDC because of the time required for the intracellular pH to cause maximal cleavage of PTX from the PDC. Moreover, it also shows that CPP-SA has a lower cytotoxicity effect on glioblastoma cells compared with PTX alone and PDC, indicating its specificity as a carrier and selectivity for integrin receptors overexpressed on the cell surface. Additionally, we have also studied the potential of our novel-designed PDC to internalize into PTX-resistant glioblastoma (U87MG-PR) cells to show cytotoxic activity upon intracellular cleavage of PTX from CPP. The data presented in Figure 3b reveal approximately 15% viability increases in U87MG-PR cells compared with parent U87MG cells. It can be seen in the inset in Figure 3b that PTX alone (EC50 = 41.3 &plusmn; 1.5 nM) showed significantly 2-fold reduced cytotoxic activity in U87MG-PR cells in comparison with our novel-designed PDC having EC50 = 20.55 &plusmn; 1.02 nM. It was also observed in Figure 3b that at lower concentrations (0-10 nM) the viable cell count was &tilde;75%; however, it significantly decreased to &tilde;20% viability with an increase in concentration (40 nM) of the test samples, highlighting the dose-dependent cytotoxicity behavior of PDC in a 24 h incubation period."	"A highly sensitive, nontoxic, hydrophilic cell-penetrating peptide (CPP = c[RGDKLAK]) was selected for the construction of an effective peptide-drug conjugate (PDC). A hydrophobic drug paclitaxel (PTX) was successfully conjugated with CPP via ester linkage with succinic acid (SA) as a pH-cleavable linker moiety. The characterization techniques employed in this study indicate the >95% purity of the resulting PDC (CPP-SA-PTX). The in vitro studies show that our proposed PDC exhibits enhanced stability (&tilde;90%) and cytotoxicity (EC50 = 8.32 &plusmn; 0.09 nM). Besides the excellent solubility of PDC in water, the PTX effect on positive &beta;-tubulin-III indicates that the drug releases retained pharmacological properties. Additionally, in vivo, therapeutic-dose treatment reveals the prominent tumor-growth inhibitory effects (2.82-3.24-fold) of PDC in tumor mice models. Subsequently, these observations confirmed that our novel-designed PDC (CPP-SA-PTX) adduct may serve as a promising therapeutic agent to treat glioblastoma."
REF00265	PDC_00022	Malaria	Plasmodium falciparum 3D7.	Obtained from the Model Organism Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	22.5 &micro;M	&micro;M	.	.	.	.	.	.	.	.	18-24 h	.	Flow cytometry assay	"The six PDIP-PQ conjugates were analyzed for their ability to inhibit the in vitro growth of P. falciparum asexual blood stage parasites (strain 3D7) in RBCs and were compared to the activity of the parent drug and peptide. We were encouraged to discover that most of the PDIP-PQ PDCs retained antiplasmodial activity similar to PDIP, with IC50 values in the low micromolar range. Notably, the various design elements probed provided valuable information regarding which PDC characteristics can be modified to improve activity."	"As a proof of concept, we aimed to produce first-generation PDCs by conjugating the antimalarial drug primaquine (PQ) onto PDIP. Although PQ is one of the few drugs without clinically relevant resistance, it does not have widespread use because it causes hemolysis in individuals who are deficient in glucose-6-phosphate dehydrogenase (G6PD), a genetic trait common in malaria-endemic areas. Furthermore, PQ is metabolized into carboxyprimaquine in the body, which does not have any activity against the parasite. The proposed PDC approach provides the potential to deliver PQ directly to the parasite, which could prevent its interaction with healthy tissues and slow the conversion of PQ into inactive byproducts. Further, the combination of the peptide and drug, each with distinct antiplasmodial mechanisms of action, provides the potential to avoid the formation of drug-resistant parasites. Herein, we report the design, synthesis, and biological evaluation of a library of PDIP-PQ conjugates. Various design elements of the PDCs were probed to investigate their effect on biological activity, including: (i) the location of the PDIP conjugation site, (ii) the hydrophilicity of the linker between the peptide and drug, (iii) the spacing between the peptide and drug, and (iv) whether the linker can be cleaved to release the drug cargo under conditions which mimic the intracellular environment of infected RBCs. This work demonstrates that conjugation within the flexible interhelix spacer of PDIP and incorporation of traceless cleavable linkersbearing either a disulfide or trioxolane moietyare important for maintaining the low micromolar potency of the PQ drug cargo against P. falciparum."
REF00265	PDC_00297	Malaria	Plasmodium falciparum 3D7.	Obtained from the Model Organism Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	12.9 &micro;M	&micro;M	.	.	.	.	.	.	.	.	18-24 h	.	Flow cytometry assay	"The six PDIP-PQ conjugates were analyzed for their ability to inhibit the in vitro growth of P. falciparum asexual blood stage parasites (strain 3D7) in RBCs and were compared to the activity of the parent drug and peptide. We were encouraged to discover that most of the PDIP-PQ PDCs retained antiplasmodial activity similar to PDIP, with IC50 values in the low micromolar range. Notably, the various design elements probed provided valuable information regarding which PDC characteristics can be modified to improve activity."	"As a proof of concept, we aimed to produce first-generation PDCs by conjugating the antimalarial drug primaquine (PQ) onto PDIP. Although PQ is one of the few drugs without clinically relevant resistance, it does not have widespread use because it causes hemolysis in individuals who are deficient in glucose-6-phosphate dehydrogenase (G6PD), a genetic trait common in malaria-endemic areas. Furthermore, PQ is metabolized into carboxyprimaquine in the body, which does not have any activity against the parasite. The proposed PDC approach provides the potential to deliver PQ directly to the parasite, which could prevent its interaction with healthy tissues and slow the conversion of PQ into inactive byproducts. Further, the combination of the peptide and drug, each with distinct antiplasmodial mechanisms of action, provides the potential to avoid the formation of drug-resistant parasites. Herein, we report the design, synthesis, and biological evaluation of a library of PDIP-PQ conjugates. Various design elements of the PDCs were probed to investigate their effect on biological activity, including: (i) the location of the PDIP conjugation site, (ii) the hydrophilicity of the linker between the peptide and drug, (iii) the spacing between the peptide and drug, and (iv) whether the linker can be cleaved to release the drug cargo under conditions which mimic the intracellular environment of infected RBCs. This work demonstrates that conjugation within the flexible interhelix spacer of PDIP and incorporation of traceless cleavable linkersbearing either a disulfide or trioxolane moietyare important for maintaining the low micromolar potency of the PQ drug cargo against P. falciparum."
REF00265	PDC_00300	Malaria	Plasmodium falciparum 3D7.	Obtained from the Model Organism Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11.3 &micro;M	&micro;M	.	.	.	.	.	.	.	.	18-24 h	.	Flow cytometry assay	"The six PDIP-PQ conjugates were analyzed for their ability to inhibit the in vitro growth of P. falciparum asexual blood stage parasites (strain 3D7) in RBCs and were compared to the activity of the parent drug and peptide. We were encouraged to discover that most of the PDIP-PQ PDCs retained antiplasmodial activity similar to PDIP, with IC50 values in the low micromolar range. Notably, the various design elements probed provided valuable information regarding which PDC characteristics can be modified to improve activity."	"As a proof of concept, we aimed to produce first-generation PDCs by conjugating the antimalarial drug primaquine (PQ) onto PDIP. Although PQ is one of the few drugs without clinically relevant resistance, it does not have widespread use because it causes hemolysis in individuals who are deficient in glucose-6-phosphate dehydrogenase (G6PD), a genetic trait common in malaria-endemic areas. Furthermore, PQ is metabolized into carboxyprimaquine in the body, which does not have any activity against the parasite. The proposed PDC approach provides the potential to deliver PQ directly to the parasite, which could prevent its interaction with healthy tissues and slow the conversion of PQ into inactive byproducts. Further, the combination of the peptide and drug, each with distinct antiplasmodial mechanisms of action, provides the potential to avoid the formation of drug-resistant parasites. Herein, we report the design, synthesis, and biological evaluation of a library of PDIP-PQ conjugates. Various design elements of the PDCs were probed to investigate their effect on biological activity, including: (i) the location of the PDIP conjugation site, (ii) the hydrophilicity of the linker between the peptide and drug, (iii) the spacing between the peptide and drug, and (iv) whether the linker can be cleaved to release the drug cargo under conditions which mimic the intracellular environment of infected RBCs. This work demonstrates that conjugation within the flexible interhelix spacer of PDIP and incorporation of traceless cleavable linkersbearing either a disulfide or trioxolane moietyare important for maintaining the low micromolar potency of the PQ drug cargo against P. falciparum."
REF00265	PDC_00301	Malaria	Plasmodium falciparum 3D7.	Obtained from the Model Organism Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.81 &micro;M	&micro;M	.	.	.	.	.	.	.	.	18-24 h	.	Flow cytometry assay	"The six PDIP-PQ conjugates were analyzed for their ability to inhibit the in vitro growth of P. falciparum asexual blood stage parasites (strain 3D7) in RBCs and were compared to the activity of the parent drug and peptide. We were encouraged to discover that most of the PDIP-PQ PDCs retained antiplasmodial activity similar to PDIP, with IC50 values in the low micromolar range. Notably, the various design elements probed provided valuable information regarding which PDC characteristics can be modified to improve activity."	"As a proof of concept, we aimed to produce first-generation PDCs by conjugating the antimalarial drug primaquine (PQ) onto PDIP. Although PQ is one of the few drugs without clinically relevant resistance, it does not have widespread use because it causes hemolysis in individuals who are deficient in glucose-6-phosphate dehydrogenase (G6PD), a genetic trait common in malaria-endemic areas. Furthermore, PQ is metabolized into carboxyprimaquine in the body, which does not have any activity against the parasite. The proposed PDC approach provides the potential to deliver PQ directly to the parasite, which could prevent its interaction with healthy tissues and slow the conversion of PQ into inactive byproducts. Further, the combination of the peptide and drug, each with distinct antiplasmodial mechanisms of action, provides the potential to avoid the formation of drug-resistant parasites. Herein, we report the design, synthesis, and biological evaluation of a library of PDIP-PQ conjugates. Various design elements of the PDCs were probed to investigate their effect on biological activity, including: (i) the location of the PDIP conjugation site, (ii) the hydrophilicity of the linker between the peptide and drug, (iii) the spacing between the peptide and drug, and (iv) whether the linker can be cleaved to release the drug cargo under conditions which mimic the intracellular environment of infected RBCs. This work demonstrates that conjugation within the flexible interhelix spacer of PDIP and incorporation of traceless cleavable linkersbearing either a disulfide or trioxolane moietyare important for maintaining the low micromolar potency of the PQ drug cargo against P. falciparum."
REF00265	PDC_00298	Malaria	Plasmodium falciparum 3D7.	Obtained from the Model Organism Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.25 &micro;M	&micro;M	.	.	.	.	.	.	4.55 h	.	18-24 h	.	Flow cytometry assay	"The six PDIP-PQ conjugates were analyzed for their ability to inhibit the in vitro growth of P. falciparum asexual blood stage parasites (strain 3D7) in RBCs and were compared to the activity of the parent drug and peptide. We were encouraged to discover that most of the PDIP-PQ PDCs retained antiplasmodial activity similar to PDIP, with IC50 values in the low micromolar range. Notably, the various design elements probed provided valuable information regarding which PDC characteristics can be modified to improve activity."	"As a proof of concept, we aimed to produce first-generation PDCs by conjugating the antimalarial drug primaquine (PQ) onto PDIP. Although PQ is one of the few drugs without clinically relevant resistance, it does not have widespread use because it causes hemolysis in individuals who are deficient in glucose-6-phosphate dehydrogenase (G6PD), a genetic trait common in malaria-endemic areas. Furthermore, PQ is metabolized into carboxyprimaquine in the body, which does not have any activity against the parasite. The proposed PDC approach provides the potential to deliver PQ directly to the parasite, which could prevent its interaction with healthy tissues and slow the conversion of PQ into inactive byproducts. Further, the combination of the peptide and drug, each with distinct antiplasmodial mechanisms of action, provides the potential to avoid the formation of drug-resistant parasites. Herein, we report the design, synthesis, and biological evaluation of a library of PDIP-PQ conjugates. Various design elements of the PDCs were probed to investigate their effect on biological activity, including: (i) the location of the PDIP conjugation site, (ii) the hydrophilicity of the linker between the peptide and drug, (iii) the spacing between the peptide and drug, and (iv) whether the linker can be cleaved to release the drug cargo under conditions which mimic the intracellular environment of infected RBCs. This work demonstrates that conjugation within the flexible interhelix spacer of PDIP and incorporation of traceless cleavable linkersbearing either a disulfide or trioxolane moietyare important for maintaining the low micromolar potency of the PQ drug cargo against P. falciparum."
REF00265	PDC_00299	Malaria	Plasmodium falciparum 3D7.	Obtained from the Model Organism Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.68 &micro;M	&micro;M	.	.	.	.	.	.	3.99 h	.	18-24 h	.	Flow cytometry assay	"The six PDIP-PQ conjugates were analyzed for their ability to inhibit the in vitro growth of P. falciparum asexual blood stage parasites (strain 3D7) in RBCs and were compared to the activity of the parent drug and peptide. We were encouraged to discover that most of the PDIP-PQ PDCs retained antiplasmodial activity similar to PDIP, with IC50 values in the low micromolar range. Notably, the various design elements probed provided valuable information regarding which PDC characteristics can be modified to improve activity."	"As a proof of concept, we aimed to produce first-generation PDCs by conjugating the antimalarial drug primaquine (PQ) onto PDIP. Although PQ is one of the few drugs without clinically relevant resistance, it does not have widespread use because it causes hemolysis in individuals who are deficient in glucose-6-phosphate dehydrogenase (G6PD), a genetic trait common in malaria-endemic areas. Furthermore, PQ is metabolized into carboxyprimaquine in the body, which does not have any activity against the parasite. The proposed PDC approach provides the potential to deliver PQ directly to the parasite, which could prevent its interaction with healthy tissues and slow the conversion of PQ into inactive byproducts. Further, the combination of the peptide and drug, each with distinct antiplasmodial mechanisms of action, provides the potential to avoid the formation of drug-resistant parasites. Herein, we report the design, synthesis, and biological evaluation of a library of PDIP-PQ conjugates. Various design elements of the PDCs were probed to investigate their effect on biological activity, including: (i) the location of the PDIP conjugation site, (ii) the hydrophilicity of the linker between the peptide and drug, (iii) the spacing between the peptide and drug, and (iv) whether the linker can be cleaved to release the drug cargo under conditions which mimic the intracellular environment of infected RBCs. This work demonstrates that conjugation within the flexible interhelix spacer of PDIP and incorporation of traceless cleavable linkersbearing either a disulfide or trioxolane moietyare important for maintaining the low micromolar potency of the PQ drug cargo against P. falciparum."
REF00263	PDC_00211	Glaucoma	Dutch belted rabbits (2-3 kg) model.	Obtained from the Model Organism Data	.	Duration of lower intraocular pressure	18 Days	Days	.	.	.	.	.	.	.	.	.	.	Hand-held rebound tonometer icareTONOVET assay	"The HR97-brimonidine conjugate provided up to 18 days of IOP lowering with a single ICM injection in normotensive rabbits, which contrasts with the 8 h-effect provided by a brimonidine eye drop."	"Sustained drug delivery strategies have many potential benefits for treating a range of diseases, particularly chronic diseases that require treatment for years. For many chronic ocular diseases, patient adherence to eye drop dosing regimens and the need for frequent intraocular injections are significant barriers to effective disease management. Here, we utilize peptide engineering to impart melanin binding properties to peptide-drug conjugates to act as a sustained-release depot in the eye. We develop a super learning-based methodology to engineer multifunctional peptides that efficiently enter cells, bind to melanin, and have low cytotoxicity. When the lead multifunctional peptide (HR97) is conjugated to brimonidine, an intraocular pressure lowering drug that is prescribed for three times per day topical dosing, intraocular pressure reduction is observed for up to 18 days after a single intracameral injection in rabbits. Further, the cumulative intraocular pressure lowering effect increases ~17-fold compared to free brimonidine injection. Engineered multifunctional peptide-drug conjugates are a promising approach for providing sustained therapeutic delivery in the eye and beyond."
REF00262	PDC_00238	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.104 &micro;M	&micro;M	.	.	.	.	Human monocytic leukemia 	THP-1 M0 type macrophages	.	.	.	.	MTS assay	"To evaluate the selective cytotoxicity of M-DM1 against M0, M1, and M2 macrophages and TAMs, the THP-1-derived macrophages were treated with different concentrations of M, DM1, and M-DM1 (0.05-10 uM) after differentiation into M0, M1, M2, and TAMs. A cytotoxicity assay was performed using the MTS assay. The half-maximal inhibitory concentrations (IC50) of M-DM1 were 2.104, 2.457, 1.488, and 1.042 uM for M0, M1, M2 macrophages, and TAMs, respectively. M-DM1 induced the apoptosis of M2-like TAMs at low concentrations compared to that observed with M2 macrophages, whereas DM1 alone did not have a cytotoxic effect on any of the macrophages."	"Recently, peptides that offer versatility in drug discovery for the successful treatment of cancers have emerged. Peptide-drug conjugates (PDCs) represent an important therapeutic strategy for increasing tumor penetration and selectivity. We previously reported that M, which is extracted from bee venom, targets M2 macrophages and improves tumor treatment in lung cancer. M is an amphipathic peptide with 26 amino acid residues (AIGAVLKVLTTGLPALISWIKRKRQQ) that specifically binds to M2-like TAMs. Mertansine (DM1) is a strong cytotoxic agent that interacts with tubulin and inhibits the assembly of tubulin into microtubules. Because it targets microtubules and inhibits cell cycle, its clinical efficacy as a potential anti-cancer agent has been studied. However, meaningful results have yet to be obtained in clinical trials, with patients also suffering several side effects, such as myelosuppression. Antibody drug conjugates (ADCs) are currently the most successful type of drug conjugates, consisting of antibody (targeting), linker (linking the antibody to the payload), and Payload (killing target cells). Payload is a cytotoxic compound and is divided into microtubule inhibitors, such as DM1, and DNA-damaging agents, such as anthracyclines. DM1 alone has not been developed as a drug but is currently used as an antibody-drug conjugate. It has been reported that the peptide LLC2B combined with DM1 exerts an anticancer effect in breast and esophageal squamous cell carcinoma, suggesting it could be developed as a potential PDC for tumor treatment. In the present study, we investigated the anti-cancer effects of M-DM1, which was synthesized using M as a carrier for targeting TAMs and DM1 as a payload. We found that M-DM1 exerts its therapeutic effects by specifically depleting M2-like TAMs in a melanoma mouse model. Through the regulation of M2-like TAMs, M-DM1 induced a significant increase in the infiltration of effector cells, such as CD8 T cells and natural killer (NK) cells, into the TME. Collectively, our results suggest that depleting M2-like TAMs in the TME by treatment with M-DM1 has immunotherapeutic effects in malignant melanoma."
REF00262	PDC_00238	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.457 &micro;M	&micro;M	.	.	.	.	Human monocytic leukemia 	THP-1 M1 type macrophages	.	.	.	.	MTS assay	"To evaluate the selective cytotoxicity of M-DM1 against M0, M1, and M2 macrophages and TAMs, the THP-1-derived macrophages were treated with different concentrations of M, DM1, and M-DM1 (0.05-10 uM) after differentiation into M0, M1, M2, and TAMs. A cytotoxicity assay was performed using the MTS assay. The half-maximal inhibitory concentrations (IC50) of M-DM1 were 2.104, 2.457, 1.488, and 1.042 uM for M0, M1, M2 macrophages, and TAMs, respectively. M-DM1 induced the apoptosis of M2-like TAMs at low concentrations compared to that observed with M2 macrophages, whereas DM1 alone did not have a cytotoxic effect on any of the macrophages."	"Recently, peptides that offer versatility in drug discovery for the successful treatment of cancers have emerged. Peptide-drug conjugates (PDCs) represent an important therapeutic strategy for increasing tumor penetration and selectivity. We previously reported that M, which is extracted from bee venom, targets M2 macrophages and improves tumor treatment in lung cancer. M is an amphipathic peptide with 26 amino acid residues (AIGAVLKVLTTGLPALISWIKRKRQQ) that specifically binds to M2-like TAMs. Mertansine (DM1) is a strong cytotoxic agent that interacts with tubulin and inhibits the assembly of tubulin into microtubules. Because it targets microtubules and inhibits cell cycle, its clinical efficacy as a potential anti-cancer agent has been studied. However, meaningful results have yet to be obtained in clinical trials, with patients also suffering several side effects, such as myelosuppression. Antibody drug conjugates (ADCs) are currently the most successful type of drug conjugates, consisting of antibody (targeting), linker (linking the antibody to the payload), and Payload (killing target cells). Payload is a cytotoxic compound and is divided into microtubule inhibitors, such as DM1, and DNA-damaging agents, such as anthracyclines. DM1 alone has not been developed as a drug but is currently used as an antibody-drug conjugate. It has been reported that the peptide LLC2B combined with DM1 exerts an anticancer effect in breast and esophageal squamous cell carcinoma, suggesting it could be developed as a potential PDC for tumor treatment. In the present study, we investigated the anti-cancer effects of M-DM1, which was synthesized using M as a carrier for targeting TAMs and DM1 as a payload. We found that M-DM1 exerts its therapeutic effects by specifically depleting M2-like TAMs in a melanoma mouse model. Through the regulation of M2-like TAMs, M-DM1 induced a significant increase in the infiltration of effector cells, such as CD8 T cells and natural killer (NK) cells, into the TME. Collectively, our results suggest that depleting M2-like TAMs in the TME by treatment with M-DM1 has immunotherapeutic effects in malignant melanoma."
REF00262	PDC_00238	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.488 &micro;M	&micro;M	.	.	.	.	Human monocytic leukemia 	THP-1 M2 type macrophages	.	.	.	.	MTS assay	"To evaluate the selective cytotoxicity of M-DM1 against M0, M1, and M2 macrophages and TAMs, the THP-1-derived macrophages were treated with different concentrations of M, DM1, and M-DM1 (0.05-10 uM) after differentiation into M0, M1, M2, and TAMs. A cytotoxicity assay was performed using the MTS assay. The half-maximal inhibitory concentrations (IC50) of M-DM1 were 2.104, 2.457, 1.488, and 1.042 uM for M0, M1, M2 macrophages, and TAMs, respectively. M-DM1 induced the apoptosis of M2-like TAMs at low concentrations compared to that observed with M2 macrophages, whereas DM1 alone did not have a cytotoxic effect on any of the macrophages."	"Recently, peptides that offer versatility in drug discovery for the successful treatment of cancers have emerged. Peptide-drug conjugates (PDCs) represent an important therapeutic strategy for increasing tumor penetration and selectivity. We previously reported that M, which is extracted from bee venom, targets M2 macrophages and improves tumor treatment in lung cancer. M is an amphipathic peptide with 26 amino acid residues (AIGAVLKVLTTGLPALISWIKRKRQQ) that specifically binds to M2-like TAMs. Mertansine (DM1) is a strong cytotoxic agent that interacts with tubulin and inhibits the assembly of tubulin into microtubules. Because it targets microtubules and inhibits cell cycle, its clinical efficacy as a potential anti-cancer agent has been studied. However, meaningful results have yet to be obtained in clinical trials, with patients also suffering several side effects, such as myelosuppression. Antibody drug conjugates (ADCs) are currently the most successful type of drug conjugates, consisting of antibody (targeting), linker (linking the antibody to the payload), and Payload (killing target cells). Payload is a cytotoxic compound and is divided into microtubule inhibitors, such as DM1, and DNA-damaging agents, such as anthracyclines. DM1 alone has not been developed as a drug but is currently used as an antibody-drug conjugate. It has been reported that the peptide LLC2B combined with DM1 exerts an anticancer effect in breast and esophageal squamous cell carcinoma, suggesting it could be developed as a potential PDC for tumor treatment. In the present study, we investigated the anti-cancer effects of M-DM1, which was synthesized using M as a carrier for targeting TAMs and DM1 as a payload. We found that M-DM1 exerts its therapeutic effects by specifically depleting M2-like TAMs in a melanoma mouse model. Through the regulation of M2-like TAMs, M-DM1 induced a significant increase in the infiltration of effector cells, such as CD8 T cells and natural killer (NK) cells, into the TME. Collectively, our results suggest that depleting M2-like TAMs in the TME by treatment with M-DM1 has immunotherapeutic effects in malignant melanoma."
REF00262	PDC_00238	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.042 &micro;M	&micro;M	.	.	.	.	Melanoma	Tumor-associated macrophages	.	.	.	.	MTS assay	"To evaluate the selective cytotoxicity of M-DM1 against M0, M1, and M2 macrophages and TAMs, the THP-1-derived macrophages were treated with different concentrations of M, DM1, and M-DM1 (0.05-10 uM) after differentiation into M0, M1, M2, and TAMs. A cytotoxicity assay was performed using the MTS assay. The half-maximal inhibitory concentrations (IC50) of M-DM1 were 2.104, 2.457, 1.488, and 1.042 uM for M0, M1, M2 macrophages, and TAMs, respectively. M-DM1 induced the apoptosis of M2-like TAMs at low concentrations compared to that observed with M2 macrophages, whereas DM1 alone did not have a cytotoxic effect on any of the macrophages."	"Recently, peptides that offer versatility in drug discovery for the successful treatment of cancers have emerged. Peptide-drug conjugates (PDCs) represent an important therapeutic strategy for increasing tumor penetration and selectivity. We previously reported that M, which is extracted from bee venom, targets M2 macrophages and improves tumor treatment in lung cancer. M is an amphipathic peptide with 26 amino acid residues (AIGAVLKVLTTGLPALISWIKRKRQQ) that specifically binds to M2-like TAMs. Mertansine (DM1) is a strong cytotoxic agent that interacts with tubulin and inhibits the assembly of tubulin into microtubules. Because it targets microtubules and inhibits cell cycle, its clinical efficacy as a potential anti-cancer agent has been studied. However, meaningful results have yet to be obtained in clinical trials, with patients also suffering several side effects, such as myelosuppression. Antibody drug conjugates (ADCs) are currently the most successful type of drug conjugates, consisting of antibody (targeting), linker (linking the antibody to the payload), and Payload (killing target cells). Payload is a cytotoxic compound and is divided into microtubule inhibitors, such as DM1, and DNA-damaging agents, such as anthracyclines. DM1 alone has not been developed as a drug but is currently used as an antibody-drug conjugate. It has been reported that the peptide LLC2B combined with DM1 exerts an anticancer effect in breast and esophageal squamous cell carcinoma, suggesting it could be developed as a potential PDC for tumor treatment. In the present study, we investigated the anti-cancer effects of M-DM1, which was synthesized using M as a carrier for targeting TAMs and DM1 as a payload. We found that M-DM1 exerts its therapeutic effects by specifically depleting M2-like TAMs in a melanoma mouse model. Through the regulation of M2-like TAMs, M-DM1 induced a significant increase in the infiltration of effector cells, such as CD8 T cells and natural killer (NK) cells, into the TME. Collectively, our results suggest that depleting M2-like TAMs in the TME by treatment with M-DM1 has immunotherapeutic effects in malignant melanoma."
REF00262	PDC_00238	Melanoma	B16-F10 tumor-bearing mouse model.	Obtained from the Model Organism Data	High Expreesion	Tumor Growth Inhibition value (TGI)	58.30%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	.	.	.	"To examine the therapeutic effects of M-DM1 in mice, we used the B16F10 tumor-bearing mouse model. We subcutaneously injected cancer cells into C57BL/6 mice and treated them with 20 nmol/kg M, DM1, or M-DM1 via intraperitoneal injections every 3 days. While slight growth inhibition was observed with M and DM1, M-DM1 was found to significantly suppress tumor growth. None of the mice showed any weight loss until the end of the study period, suggesting that there were no significant toxicities due to the drug treatments. At 21 days after tumor cell inoculation, the mice were sacrificed, and tumor volumes and weights were measured. A marked decrease in the tumor volumes and weights was observed in the M-DM1-treated mice group compared to that in the other groups. In addition, we determined the survival rate of B16-bearing mice following treatment with each peptide. The median survival of the M-DM1 group was significantly higher than that of the other groups. These results demonstrate that M-DM1 is highly effective in inhibiting tumor growth and prolonging survival in melanoma."	"Recently, peptides that offer versatility in drug discovery for the successful treatment of cancers have emerged. Peptide-drug conjugates (PDCs) represent an important therapeutic strategy for increasing tumor penetration and selectivity. We previously reported that M, which is extracted from bee venom, targets M2 macrophages and improves tumor treatment in lung cancer. M is an amphipathic peptide with 26 amino acid residues (AIGAVLKVLTTGLPALISWIKRKRQQ) that specifically binds to M2-like TAMs. Mertansine (DM1) is a strong cytotoxic agent that interacts with tubulin and inhibits the assembly of tubulin into microtubules. Because it targets microtubules and inhibits cell cycle, its clinical efficacy as a potential anti-cancer agent has been studied. However, meaningful results have yet to be obtained in clinical trials, with patients also suffering several side effects, such as myelosuppression. Antibody drug conjugates (ADCs) are currently the most successful type of drug conjugates, consisting of antibody (targeting), linker (linking the antibody to the payload), and Payload (killing target cells). Payload is a cytotoxic compound and is divided into microtubule inhibitors, such as DM1, and DNA-damaging agents, such as anthracyclines. DM1 alone has not been developed as a drug but is currently used as an antibody-drug conjugate. It has been reported that the peptide LLC2B combined with DM1 exerts an anticancer effect in breast and esophageal squamous cell carcinoma, suggesting it could be developed as a potential PDC for tumor treatment. In the present study, we investigated the anti-cancer effects of M-DM1, which was synthesized using M as a carrier for targeting TAMs and DM1 as a payload. We found that M-DM1 exerts its therapeutic effects by specifically depleting M2-like TAMs in a melanoma mouse model. Through the regulation of M2-like TAMs, M-DM1 induced a significant increase in the infiltration of effector cells, such as CD8 T cells and natural killer (NK) cells, into the TME. Collectively, our results suggest that depleting M2-like TAMs in the TME by treatment with M-DM1 has immunotherapeutic effects in malignant melanoma."
REF00261	PDC_00324	Colorectal cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	375.5 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	CT26 cell	.	.	24 h	.	Ez Cytox cell viability assay kit assay	"Cell viability and corresponding IC50 values of CT26 tumor cells in the concentration range of 0.1-1000 &mu;M RR-BA, RR peptides, or BA were measured after 24 h and 48 h incubation. The 24 h cytotoxicity IC50 value of RR peptide and BA is NA and RR-BA is 375.5 &mu;M. The 48 h cytotoxicity IC50 value of RR peptide and BA is NA and RR-BA is 149.5 &mu;M. *** Denotes statistically significant differences in a comparison of RR-BA with RR peptides and BA (*** p < 0.001). Results represent means &plusmn; S.D."	"Here, we developed a cathepsin B inhibitor using a peptide and bile acid for anticancer therapy. Among the peptide sequences that cathepsin B can recognize, positively charged Arg-Arg (RR) was used as a cathepsin-B-specific peptide without any linkers. A hydrophobic bile acid (BA) was coupled via amide linkages to further enhance the inhibitory effects of the peptides. Out of several types of bile acids, ursodeoxycholic acid (UDCA), a safe drug approved by the US Food and Drug Administration (FDA), was used for this study. The nano-sized Arg-Arg and BA conjugate (RR-BA) can be self-assembled in an aqueous solution, forming nanoparticles due to the strong positive charge and the hydrophobicity of bile acids. This pharmaceutical substance has shown promising results in mouse colorectal cancer (CT26) cell treatment and animal experiments. This type of pharmaceutical therapy could be a potential option for cancer treatment."
REF00261	PDC_00324	Colorectal cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	149.5 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	CT26 cell	.	.	48 h	.	Ez Cytox cell viability assay kit	"Cell viability and corresponding IC50 values of CT26 tumor cells in the concentration range of 0.1-1000 &mu;M RR-BA, RR peptides, or BA were measured after 24 h and 48 h incubation. The 24 h cytotoxicity IC50 value of RR peptide and BA is NA and RR-BA is 375.5 &mu;M. The 48 h cytotoxicity IC50 value of RR peptide and BA is NA and RR-BA is 149.5 &mu;M. *** Denotes statistically significant differences in a comparison of RR-BA with RR peptides and BA (*** p < 0.001). Results represent means &plusmn; S.D."	"Here, we developed a cathepsin B inhibitor using a peptide and bile acid for anticancer therapy. Among the peptide sequences that cathepsin B can recognize, positively charged Arg-Arg (RR) was used as a cathepsin-B-specific peptide without any linkers. A hydrophobic bile acid (BA) was coupled via amide linkages to further enhance the inhibitory effects of the peptides. Out of several types of bile acids, ursodeoxycholic acid (UDCA), a safe drug approved by the US Food and Drug Administration (FDA), was used for this study. The nano-sized Arg-Arg and BA conjugate (RR-BA) can be self-assembled in an aqueous solution, forming nanoparticles due to the strong positive charge and the hydrophobicity of bile acids. This pharmaceutical substance has shown promising results in mouse colorectal cancer (CT26) cell treatment and animal experiments. This type of pharmaceutical therapy could be a potential option for cancer treatment."
REF00259	PDC_00250	Inflammation	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	human coronary artery endothelial cell	Human coronary artery endothelial cell	.	.	1 h	.	Propidium iodide (PI) assay	"We next determined whether treatment of HCAEC and Molt-3 T cells with peptides, MTX, and MTX-peptide conjugates resulted in inhibition of cell proliferation. Both HCAEC and Molt-3 T cells were affected by test compound in different levels. None of the molecules caused growth stimulation or total culture extinction. A net cell killing of HCAEC was observed upon treatment with MTX at all test concentrations while MTX affected net killing at &ge;1.0 uM in Molt-3 T cells. The MTX-peptide conjugates were less toxic than MTX. In HCAEC, the net cell killing was at lower concentration for MTX at &ge;0.1 uM compared to MTX-peptide conjugates at &ge;500 uM. The net cell killing of Molt-3 T cells was found at &ge;1.0 uM for MTX and &ge;50 uM for MTX-peptide conjugates. For all test concentrations, the conjugates only resulted in HCAEC partial growth inhibition. For Molt-3 T cells, a total growth inhibition emerged at 100 uM for cLABL and cLBEL; however, 500 uM cLABL and cLBEL did not cause total cell killing for T cells."	"In this study, cLABL and cLBEL peptides were linked to methotrexate (MTX) to produce MTX-cLABL and MTX-cLBEL conjugates. The goal was to target MTX to human coronary artery endothelial cells (HCAEC) via the ICAM-1 receptor to lower MTX toxicity and side effects. The biological abilities of MTX-cLABL, MTX-cLBEL, cLABL, cLBEL, and MTX were compared by their activities to inhibit binding of anti-ICAM-1 mAb to ICAM-1 on the surface of HCAEC. In addition, these molecules were compared in inhibiting T cell adhesion to HCAEC monolayers. Finally, their activities in suppressing IL-6 and IL-8 production as inflammatory cytokines were determined. The toxicities of MTX-cLABL and MTX-cLBEL conjugates were also determined relative to MTX alone as well as cLABL and cLBEL peptides."
REF00259	PDC_00251	Inflammation	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	human coronary artery endothelial cell	Human coronary artery endothelial cell	.	.	1 h	.	Propidium iodide (PI) assay	"We next determined whether treatment of HCAEC and Molt-3 T cells with peptides, MTX, and MTX-peptide conjugates resulted in inhibition of cell proliferation. Both HCAEC and Molt-3 T cells were affected by test compound in different levels. None of the molecules caused growth stimulation or total culture extinction. A net cell killing of HCAEC was observed upon treatment with MTX at all test concentrations while MTX affected net killing at &ge;1.0 uM in Molt-3 T cells. The MTX-peptide conjugates were less toxic than MTX. In HCAEC, the net cell killing was at lower concentration for MTX at &ge;0.1 uM compared to MTX-peptide conjugates at &ge;500 uM. The net cell killing of Molt-3 T cells was found at &ge;1.0 uM for MTX and &ge;50 uM for MTX-peptide conjugates. For all test concentrations, the conjugates only resulted in HCAEC partial growth inhibition. For Molt-3 T cells, a total growth inhibition emerged at 100 uM for cLABL and cLBEL; however, 500 uM cLABL and cLBEL did not cause total cell killing for T cells."	"In this study, cLABL and cLBEL peptides were linked to methotrexate (MTX) to produce MTX-cLABL and MTX-cLBEL conjugates. The goal was to target MTX to human coronary artery endothelial cells (HCAEC) via the ICAM-1 receptor to lower MTX toxicity and side effects. The biological abilities of MTX-cLABL, MTX-cLBEL, cLABL, cLBEL, and MTX were compared by their activities to inhibit binding of anti-ICAM-1 mAb to ICAM-1 on the surface of HCAEC. In addition, these molecules were compared in inhibiting T cell adhesion to HCAEC monolayers. Finally, their activities in suppressing IL-6 and IL-8 production as inflammatory cytokines were determined. The toxicities of MTX-cLABL and MTX-cLBEL conjugates were also determined relative to MTX alone as well as cLABL and cLBEL peptides."
REF00259	PDC_00250	Inflammation	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	500 &micro;M	&micro;M	.	.	.	.	Adult T acute lymphoblastic leukemia	Molt-3 T cell	.	.	1 h	.	Propidium iodide (PI) assay	"We next determined whether treatment of HCAEC and Molt-3 T cells with peptides, MTX, and MTX-peptide conjugates resulted in inhibition of cell proliferation. Both HCAEC and Molt-3 T cells were affected by test compound in different levels. None of the molecules caused growth stimulation or total culture extinction. A net cell killing of HCAEC was observed upon treatment with MTX at all test concentrations while MTX affected net killing at &ge;1.0 uM in Molt-3 T cells. The MTX-peptide conjugates were less toxic than MTX. In HCAEC, the net cell killing was at lower concentration for MTX at &ge;0.1 uM compared to MTX-peptide conjugates at &ge;500 uM. The net cell killing of Molt-3 T cells was found at &ge;1.0 uM for MTX and &ge;50 uM for MTX-peptide conjugates. For all test concentrations, the conjugates only resulted in HCAEC partial growth inhibition. For Molt-3 T cells, a total growth inhibition emerged at 100 uM for cLABL and cLBEL; however, 500 uM cLABL and cLBEL did not cause total cell killing for T cells."	"In this study, cLABL and cLBEL peptides were linked to methotrexate (MTX) to produce MTX-cLABL and MTX-cLBEL conjugates. The goal was to target MTX to human coronary artery endothelial cells (HCAEC) via the ICAM-1 receptor to lower MTX toxicity and side effects. The biological abilities of MTX-cLABL, MTX-cLBEL, cLABL, cLBEL, and MTX were compared by their activities to inhibit binding of anti-ICAM-1 mAb to ICAM-1 on the surface of HCAEC. In addition, these molecules were compared in inhibiting T cell adhesion to HCAEC monolayers. Finally, their activities in suppressing IL-6 and IL-8 production as inflammatory cytokines were determined. The toxicities of MTX-cLABL and MTX-cLBEL conjugates were also determined relative to MTX alone as well as cLABL and cLBEL peptides."
REF00259	PDC_00251	Inflammation	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	500 &micro;M	&micro;M	.	.	.	.	Adult T acute lymphoblastic leukemia	Molt-3 T cell	.	.	1 h	.	Propidium iodide (PI) assay	"We next determined whether treatment of HCAEC and Molt-3 T cells with peptides, MTX, and MTX-peptide conjugates resulted in inhibition of cell proliferation. Both HCAEC and Molt-3 T cells were affected by test compound in different levels. None of the molecules caused growth stimulation or total culture extinction. A net cell killing of HCAEC was observed upon treatment with MTX at all test concentrations while MTX affected net killing at &ge;1.0 uM in Molt-3 T cells. The MTX-peptide conjugates were less toxic than MTX. In HCAEC, the net cell killing was at lower concentration for MTX at &ge;0.1 uM compared to MTX-peptide conjugates at &ge;500 uM. The net cell killing of Molt-3 T cells was found at &ge;1.0 uM for MTX and &ge;50 uM for MTX-peptide conjugates. For all test concentrations, the conjugates only resulted in HCAEC partial growth inhibition. For Molt-3 T cells, a total growth inhibition emerged at 100 uM for cLABL and cLBEL; however, 500 uM cLABL and cLBEL did not cause total cell killing for T cells."	"In this study, cLABL and cLBEL peptides were linked to methotrexate (MTX) to produce MTX-cLABL and MTX-cLBEL conjugates. The goal was to target MTX to human coronary artery endothelial cells (HCAEC) via the ICAM-1 receptor to lower MTX toxicity and side effects. The biological abilities of MTX-cLABL, MTX-cLBEL, cLABL, cLBEL, and MTX were compared by their activities to inhibit binding of anti-ICAM-1 mAb to ICAM-1 on the surface of HCAEC. In addition, these molecules were compared in inhibiting T cell adhesion to HCAEC monolayers. Finally, their activities in suppressing IL-6 and IL-8 production as inflammatory cytokines were determined. The toxicities of MTX-cLABL and MTX-cLBEL conjugates were also determined relative to MTX alone as well as cLABL and cLBEL peptides."
REF00257	PDC_00235	Colorectal cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.047 &micro;M	&micro;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	48 h	.	MTT assay	"To determine the activity of the compounds, we analyzed the effects of them on cell growth and migration in HCT116 cells. We found that LWJ-M30 displayed significant inhibition of cell proliferation and clone formation ability. The IC50 of LWJ-M30 was 0.047 uM which was close to DM1 (0.026 uM). According to the results of wound-healing assay and transwell migration assay, LWJ-M30 also dramatically showed a inhibitory effect on cells migration. These results suggested that LWJ-M30 could inhibit the cells proliferation and migration."	"Given these findings, we employed tissue-specific drug delivery approaches PDC to overcome those adverse effects. Several TfR-targeted peptides sequence with different affinity have been reported, so we synthesized a series of TfR-targeted peptide-DM1 conjugates for screening the effects of TfR-targeted drug candidates. It is speculated that the conjugates can specifically target tumor with high expression of TfR and can be uptake more than that of the normal cells. We succeeded found LWJ-M30, a conjugate of DM1 and B6, had a significant therapeutic effect after preliminary screening. In order to further reveal the improved therapeutic effects and mechanism of the LWJ-M30 on cancer with high TfR expression, in this study, we investigated the role of the LWJ-M30 in the targeted therapy for colorectal cancer in vitro and in vivo and explored the therapeutic mechanism."
REF00255	PDC_00319	Triple-negative breast cancer	Female BALB/c mice 4T1-mCherry-Luc cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	43.24%	%	.	.	.	.	Malignant neoplasms of the mouse mammary gland	4T1-mCherry-Luc cell	.	.	16 d	10.6 mg/kg	.	"The mice TNBC 4T1-mCherry-Luc model was constructed by subcutaneous inoculation to study the anti-tumor effect of PTX-SM-TAR NPs in vivo. 4T1-mCherry-Luc cells reacted with D-luciferin potassium salt to produce bioluminescence, which was determined by an IVIS spectrum imaging system. The intensity of the fluorescence signal is related to tumor size, hence tumor growth in mice can be monitored in real-time. As shown in Figure 9a, the tumor growth rate of the PTX-SM-TAR NPs group was lower than that of the NS, TAR, and PTX groups. At the end of the experiment, the tumor tissue was weighed, and the results were consistent with the trend of fluorescence intensity. The tumor inhibition rate was 43.24% in the PTX-SM-TAR NPs, 28.47% in the PTX, and 7.81% in the TAR. The tumor inhibitory effect of the PTX-SM-TAR NPs group was stronger than that of the PTX group, and the difference was significant."	"Triple-negative breast cancer (TNBC) is an extremely aggressive subtype associated with a poor prognosis. At present, the treatment for TNBC mainly relies on surgery and traditional chemotherapy. As a key component in the standard treatment of TNBC, paclitaxel (PTX) effectively inhibits the growth and proliferation of tumor cells. However, the application of PTX in clinical treatment is limited due to its inherent hydrophobicity, weak penetrability, nonspecific accumulation, and side effects. To counter these problems, we constructed a novel PTX conjugate based on the peptide-drug conjugates (PDCs) strategy. In this PTX conjugate, a novel fused peptide TAR consisting of a tumor-targeting peptide, A7R, and a cell-penetrating peptide, TAT, is used to modify PTX. After modification, this conjugate is named PTX-SM-TAR, which is expected to improve the specificity and penetrability of PTX at the tumor site. Depending on hydrophilic TAR peptide and hydrophobic PTX, PTX-SM-TAR can self-assemble into nanoparticles and improve the water solubility of PTX. In terms of linkage, the acid- and esterase-sensitive ester bond was used as the linking bond, with which PTX-SM-TAR NPs could remain stable in the physiological environment, whereas PTX-SM-TAR NPs could be broken and PTX be released at the tumor site. A cell uptake assay showed that PTX-SM-TAR NPs were receptor-targeting and could mediate endocytosis by binding to NRP-1. The vascular barrier, transcellular migration, and tumor spheroids experiments showed that PTX-SM-TAR NPs exhibit great transvascular transport and tumor penetration ability. In vivo experiments, PTX-SM-TAR NPs showed higher antitumor effects than PTX. As a result, PTX-SM-TAR NPs may overcome the shortcomings of PTX and present a new transcytosable and targeted delivery system for PTX in TNBC treatment."
REF00254	PDC_00139	Breast cancer	SKBR-3 cells female BALB/c mice xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	51.1 &plusmn; 3.1%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	14 days	5 mg/kg	.	"In vivo anti-tumor studies were evaluated by using SKBR-3 xenografted (BALB/c nude) mice treated with the PDC, free DOX, or saline. Figure 5a demonstrates that the PDC had a much more powerful anti-tumor effect than free DOX, reducing tumor growth by 51.1 &plusmn; 3.1% on day 14 post treatment, while free DOX only achieved a 23.13 &plusmn; 2.4% reduction. Additionally, the PDC had a significantly higher tumor weight inhibition of 57.5 &plusmn; 3.4% compared to free DOX."	"Tumor-targeting peptide-drug conjugates (PDCs) have become a focus of research in recent years. However, due to the instability of peptides and their short in vivo effective half-life, they have limited clinical application. Herein, we propose a new DOX PDC based on a homodimer HER-2-targeting peptide and acid-sensitive hydrazone bond, which could enhance the anti-tumor effect of DOX and reduce systemic toxicities. The PDC could accurately deliver DOX into HER2-positive SKBR-3 cells, with it showing 2.9 times higher cellular uptake than free DOX and enhanced cytotoxicity with respect to IC50of 140 nM (vs. 410 nM for free DOX). In vitro assays showed that the PDC had high cellular internalization efficiency and cytotoxicity. In vivo anti-tumor experiments indicated that the PDC could significantly inhibit the growth of HER2-positive breast cancer xenografts in mice and reduce the side effects of DOX. In summary, we constructed a novel PDC molecule targeting HER2-positive tumors, which may overcome some deficiencies of DOX in breast cancer therapy."
REF00254	PDC_00139	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	140 nM	nM	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	24 h	.	CCK8 assay	"Tumor-targeting peptide-drug conjugates (PDCs) have become a focus of research in recent years. However, due to the instability of peptides and their short in vivo effective half-life, they have limited clinical application. Herein, we propose a new DOX PDC based on a homodimer HER-2-targeting peptide and acid-sensitive hydrazone bond, which could enhance the anti-tumor effect of DOX and reduce systemic toxicities. The PDC could accurately deliver DOX into HER2-positive SKBR-3 cells, with it showing 2.9 times higher cellular uptake than free DOX and enhanced cytotoxicity with respect to IC50of 140 nM (vs. 410 nM for free DOX). In vitro assays showed that the PDC had high cellular internalization efficiency and cytotoxicity. In vivo anti-tumor experiments indicated that the PDC could significantly inhibit the growth of HER2-positive breast cancer xenografts in mice and reduce the side effects of DOX. In summary, we constructed a novel PDC molecule targeting HER2-positive tumors, which may overcome some deficiencies of DOX in breast cancer therapy."	"Tumor-targeting peptide-drug conjugates (PDCs) have become a focus of research in recent years. However, due to the instability of peptides and their short in vivo effective half-life, they have limited clinical application. Herein, we propose a new DOX PDC based on a homodimer HER-2-targeting peptide and acid-sensitive hydrazone bond, which could enhance the anti-tumor effect of DOX and reduce systemic toxicities. The PDC could accurately deliver DOX into HER2-positive SKBR-3 cells, with it showing 2.9 times higher cellular uptake than free DOX and enhanced cytotoxicity with respect to IC50of 140 nM (vs. 410 nM for free DOX). In vitro assays showed that the PDC had high cellular internalization efficiency and cytotoxicity. In vivo anti-tumor experiments indicated that the PDC could significantly inhibit the growth of HER2-positive breast cancer xenografts in mice and reduce the side effects of DOX. In summary, we constructed a novel PDC molecule targeting HER2-positive tumors, which may overcome some deficiencies of DOX in breast cancer therapy."
REF00253	PDC_00155	Cervical carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	5 &plusmn; 0.4 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00155	Chronic myeloid leukemia	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	5 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	Chronic myeloid leukemia	K562 cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00155	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	8 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00155	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	5 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00155	Cervical carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	11 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00155	Chronic myeloid leukemia	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	10 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	Chronic myeloid leukemia	K562 cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00155	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	16 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00155	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	10 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00155	Cervical carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	10-50 min	.	48 h	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00155	Chronic myeloid leukemia	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	12 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Chronic myeloid leukemia	K562 cell	10-50 min	.	48 h	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00155	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11 &plusmn; 0.4 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	10-50 min	.	48 h	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00155	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	10-50 min	.	48 h	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00156	Cervical carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	5 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00156	Chronic myeloid leukemia	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	12 &plusmn; 0.9 &micro;M	&micro;M	.	.	.	.	Chronic myeloid leukemia	K562 cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00156	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	8 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00156	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	4 &plusmn; 0.4 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00156	Cervical carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	11 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00156	Chronic myeloid leukemia	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	23 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Chronic myeloid leukemia	K562 cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00156	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	15 &plusmn; 0.7 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00156	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	9 &plusmn; 0.4 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	10-50 min	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00156	Cervical carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9 &plusmn; 0.2 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	10-50 min	.	48 h	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00156	Chronic myeloid leukemia	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	17 &plusmn; 0.5 &micro;M	&micro;M	.	.	.	.	Chronic myeloid leukemia	K562 cell	10-50 min	.	48 h	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00156	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10 &plusmn; 0.3 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	10-50 min	.	48 h	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00156	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3 &plusmn; 0.4 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	10-50 min	.	48 h	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00157	Cervical carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	100 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	> 48 h	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00157	Chronic myeloid leukemia	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	100 &micro;M	&micro;M	.	.	.	.	Chronic myeloid leukemia	K562 cell	> 48 h	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00157	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	100 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	> 48 h	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00157	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal growth inhibition concentration (GI50)	33 &plusmn; 0.9 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	> 48 h	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00157	Cervical carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	100 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	> 48 h	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00157	Chronic myeloid leukemia	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	100 &micro;M	&micro;M	.	.	.	.	Chronic myeloid leukemia	K562 cell	> 48 h	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00157	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	100 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	> 48 h	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00157	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	64 &plusmn; 0.9 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	> 48 h	.	.	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00157	Cervical carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	> 48 h	.	48 h	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00157	Chronic myeloid leukemia	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Chronic myeloid leukemia	K562 cell	> 48 h	.	48 h	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00157	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	> 48 h	.	48 h	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00253	PDC_00157	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	45 &plusmn; 1.0 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	> 48 h	.	48 h	.	MTT assay	"The cytotoxic activity of JH-VII-139-1 and JH-VII-139-1-c(RGDyK) hybrid compounds was evaluated at different concentrations (0.5-50 uM) over a panel of cell lines including HeLa cervical cancer, MCF7 mammary carcinoma, the triple-negative breast cancer MDA-MB-231 and K562 lymphoblast cells. Integrin receptors are highly overexpressed on the surface of many types of cancer. The metastatic breast cancer cell lines MDA-MB-435 and MCF-7, as well as HeLa cells, express high levels of V3 integrins. On the other hand, K562 cells express very low levels of V3 integrins. The cytotoxic and cytostatic activities of the JH-VII-139-1-c(RGDyK) hybrid compounds were estimated by three concentration-dependent parameters: GI50 (concentration that results in 50% growth inhibition), TGI (concentration that results in total growth inhibition or cytostatic effect), and IC50 (concentration that results in 50% growth cytotoxic effect). JH-VII-139-1 and the hybrid compounds, geo75 and geo77, showed a significant cytostatic (GI50 = 4-12 uM) and cytotoxic (IC50 = 3-18 uM) effect against HeLa, MCF-7, MDA-MB-231 and K562 cancer cells. The most active compound was geo77, showing IC50 and GI50 values of 3 uM and 4 uM, respectively in the most sensitive cell line MCF-7. Geo85 exhibited a slightly cytostatic effect (GI50 = 33 uM), with a minor cytotoxicity (IC50 = 45 uM) only against MCF-7 cells."	"Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the &beta;3targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates,geo75andgeo77exhibited antiproliferative effects with low micromolar IC50values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases."
REF00251	PDC_00273	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	22.80 &plusmn; 3.12 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00274	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.29 &plusmn; 3.41 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00275	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.28 &plusmn; 0.13 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00276	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	20.98 &plusmn; 0.55 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00277	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	18.29 &plusmn; 1.46 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00278	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.15 &plusmn; 0.18 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00279	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11.74 &plusmn; 0.09 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00280	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	18.96 &plusmn; 3.23 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00281	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.31 &plusmn; 0.01 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00282	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.35 &plusmn; 0.32 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00283	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.88 &plusmn; 2.82 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00273	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11.45 &plusmn; 1.53 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00274	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	12.72 &plusmn; 1.22 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00275	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.78 &plusmn; 0.97 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00276	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.37 &plusmn; 1.28 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00277	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11.62 &plusmn; 3.33 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00278	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.87 &plusmn; 0.09 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00279	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	19.14 &plusmn; 0.49 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00280	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	25 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00281	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	21.21 &plusmn; 5.36 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00282	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.86 &plusmn; 0.75 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00283	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.64 &plusmn; 0.25 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00273	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11.83 &plusmn; 2.50 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00274	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.98 &plusmn; 2.10 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00275	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.55 &plusmn; 0.76 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00276	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.73 &plusmn; 0.24 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00277	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.69 &plusmn; 0.17 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00278	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.38 &plusmn; 0.33 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00279	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.57 &plusmn; 1.61 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00280	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	25 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00281	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.08 &plusmn; 0.09 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00282	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.22 &plusmn; 0.19 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00283	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	18.04 &plusmn; 3.01 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	24 h	.	MTT assay	"The cytostatic effect of the conjugates and the free peptides was evaluated on the three mentioned human cancer cell lines expressing GRP-R. The free Dau was used as a positive control for comparison purposes; it displays an IC50 in the high nanomolar range. Overall, the conjugates containing the LRRY spacer have a higher cytostatic effect than the ones with the GFLG spacer. L1, which has the original BBN (7-14) sequence, and L5, bearing a D-Phe in position 6 and the Sta13-Leu14 bond at the C-terminus, shows the best activity in all three cell lines, with IC50 values in the low micromolar range. The Gly11/-Ala11 and Leu13-Met14/Sta13-Nle14 substitutions, which led to a new BBN (6-14) peptide sequence, held by the conjugate L6, affect the activity only slightly. Contrarily, the two free peptides, bearing the sequences of L5 and L6, do not show any activity on any of the cell lines. The lack of toxicity of the conjugates on healthy cells was checked on MRC-5 human fibroblasts, proving that they are non-toxic on non-cancerous cells."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00273	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00274	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00275	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00276	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	23.33 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00277	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00278	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	18.67 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00279	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	18.27 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00280	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00281	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00282	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	15.87 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00283	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	15.47 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00273	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00274	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	17.04 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00275	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	22.59 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00276	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	20.22 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00277	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00278	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	11.63 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00279	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	21.58 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00280	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	24.59 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00281	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00282	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	8.96 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00283	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	4.15 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-453 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00273	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00274	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	10.5 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00275	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00276	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00277	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00278	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	22.92 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00279	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	20.87 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00280	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00281	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	25 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00282	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	12.35 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00251	PDC_00283	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Uptake Concentration (UC50)	16.09 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"We quantified the ability of the produced PDCs to promote the internalisation of daunorubicin after binding to GRP-R by flow cytometry. Each bioconjugate was incubated for 1.5 h in four concentrations (25 uM, 12.5 uM, 6.25 uM and 3.125 uM), with the three cell lines that we have also used for the evaluation of the cytostatic effect. For better comparison, the uptake was described as the necessary concentration to internalise 50% of the compound (UC50). The uptake reflects the GRP-R protein expression: the lower UC50 values, hence the highest uptakes, are noticed in the human breast cancer cell line MDA-MB-453, whereas they are comparable in the two other cell lines. As far as the internalisation of the individual conjugates is concerned, L5 and L6 are the most promising ones in these three cell lines. Notably, both hold the LRRY spacer and the Sta13. L1 and L2 have satisfactory UC50s, too. On the other hand, majority of the conjugates with the GFLG spacer are poorly internalised."	"We decided to select some of the described peptides bearing the mentioned substitutions and having affirmed affinity for GRP-R in the low nanomolar range, together with the original BBN, and use them as targeting moiety to deliver a cytotoxic payload, daunorubicin (Dau), to prostate and breast cancers. Compared to the BBN sequence, our targeting peptides are elongated by a D-Phe in position 6 and comprise substitutions in positions 11, 13 and 14. Starting from these variations, we have also generated a new sequence: [D-Phe6, &beta;-Ala11, Sta13, Nle14]BBN. The bombesin analogues have been published in the works of different research groups throughout many years, however, a direct comparison between them in terms of drug delivery has never been done. Once the targeting peptides bind to receptors that are overexpressed on the surface of cancer cells, such as GRP-R, the PDC can be carried inside the cells via receptor-mediated endocytosis. Briefly, the receptor-ligand complex internalises via a special, coated vesicle that later fuses with an early endosome and matures into a late endosome. After the late endosome fuses with a lysosome, the PDC is also digested, the drug is released into the cytoplasm and binds to its target compartment inside the cell. To ensure this release, we have decided to insert cathepsin B cleavable tetrapeptide linkers, namely either GFLG or LRRY, between the homing peptide and Dau. Indeed, cathepsin B is highly expressed by lysosomes and can cleave between Gly-Phe and Leu-Arg, liberating the active metabolites Dau=Aoa-Gly-OH or Dau=Aoa-Leu-OH. Dau is part of the family of anthracyclines and elicits its cytostatic activity by intercalating between DNA base pairs. This prevents the topoisomerase II from resealing the DNA double helix, resulting in reduced cell proliferation. Its attachment to a peptide can be easily performed through an oxime linkage in a very simple and straightforward reaction that occurs between an aminooxy moiety and the C13 ketone on Dau. The high yields of the reaction are advantageous, especially when it comes to the production of an increased amount of conjugate for in vivo studies. Furthermore, thanks to its intrinsic fluorescence, it is possible to evaluate the internalisation of the Dau-conjugates by fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), without the need to produce alternative peptide conjugates. To the best of our knowledge, so far, the delivery of a payload by bombesin-related peptides has only been studied using fluorescent molecules such as TAMRA, radioligands or nanocarriers. Drugs were attached to the peptides less often, and mainly using the original or truncated bombesin sequence instead of more promising analogues, or ones that are non-selective for GRP-R. Oppositely, investigating features such as the cellular uptake directly, through a conjugate attached to a chemotherapeutic, gives the most realistic picture of the success of a homing peptide acting as a drug carrier. Thus, the generated structures provide valuable tools for the selection of targeting peptides, aiming to the further development of new tumour-selective conjugates containing different linker-payload systems."
REF00250	PDC_00218	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	30.2 &plusmn; 6.4 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U87 cell	.	.	72 h	.	MTT assay	"The in vitro cytostatic effect of the synthesized peptide (1) and daunomycin-peptide conjugates (2-8) was investigated on U87 human glioblastoma cells. The cells were treated with the peptide and conjugates at different concentrations (0.05-50 uM) for 24 h, and after a washing step, the cells were incubated for another 48 h at 37 C. The cytostatic effect of the compounds was determined using the MTT test. The measured IC50values are shown in. The free Angiopep-2 did not show any effect on tumor cells up to a 50 &mu;M concentration. However, no clear correlation could be obtained between the number of the daunomycin and the cytostatic efficacy. Among the conjugates with only one Dau, compound3,in which Dau was attached to theN-terminus, showed the highest in vitro cytostatic effect on glioblastoma cells. When the Dau was conjugated to the Lys side chain in position 15 (compound2), the effect decreased significantly, and conjugate4was also not significantly better. In case of conjugates with two drug molecules, a similar tendency was observed. Compound7,with Dau at theN-terminus and on the Lys side chain in position 10, showed the highest activity. When the Lys side chains were used as conjugation sites, the formed compound (6) had moderate activity on U87 cells. Surprisingly, conjugate5,with Dau at theN-terminus and Lys side chain in position 15, showed the lowest efficacy on the U87 cells. Compound8,with three Dau, showed moderate activity. Thus, the effectiveness of Angiopep-2-daunomycin conjugates does not primarily depend on the number of drug molecules, but rather on their position within the molecule."	"The blood-brain barrier (BBB) is a semipermeable system, and, therefore, most of the active substances are poorly transported through this barrier, resulting in decreased therapeutic effects. Angiopep-2 (TFFYGGSRGKRNNFKTEEY) is a peptide ligand of low-density lipoprotein receptor-related protein-1 (LRP1), which can cross the BBB via receptor-mediated transcytosis and simultaneously target glioblastomas. Angiopep-2 contains three amino groups that have previously been used to produce drug-peptide conjugates, although the role and importance of each position have not yet been investigated. Thus, we studied the number and position of drug molecules in Angiopep-2 based conjugates. Conjugates containing one, two, and three daunomycin molecules conjugated via oxime linkage in all possible variations were prepared. The in vitro cytostatic effect and cellular uptake of the conjugates were investigated on U87 human glioblastoma cells. Degradation studies in the presence of rat liver lysosomal homogenates were also performed in order for us to better understand the structure-activity relationship and to determine the smallest metabolites. Conjugates with the best cytostatic effects had a drug molecule at the N-terminus. We demonstrated that the increasing number of drug molecules does not necessarily increase the efficacy of the conjugates, and proved that modification of the different conjugation sites results in differing biological effectiveness."
REF00250	PDC_00115	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.9 &plusmn; 2.8 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U87 cell	.	.	72 h	.	MTT assay	"The in vitro cytostatic effect of the synthesized peptide (1) and daunomycin-peptide conjugates (2-8) was investigated on U87 human glioblastoma cells. The cells were treated with the peptide and conjugates at different concentrations (0.05-50 uM) for 24 h, and after a washing step, the cells were incubated for another 48 h at 37 C. The cytostatic effect of the compounds was determined using the MTT test. The measured IC50values are shown in. The free Angiopep-2 did not show any effect on tumor cells up to a 50 &mu;M concentration. However, no clear correlation could be obtained between the number of the daunomycin and the cytostatic efficacy. Among the conjugates with only one Dau, compound3,in which Dau was attached to theN-terminus, showed the highest in vitro cytostatic effect on glioblastoma cells. When the Dau was conjugated to the Lys side chain in position 15 (compound2), the effect decreased significantly, and conjugate4was also not significantly better. In case of conjugates with two drug molecules, a similar tendency was observed. Compound7,with Dau at theN-terminus and on the Lys side chain in position 10, showed the highest activity. When the Lys side chains were used as conjugation sites, the formed compound (6) had moderate activity on U87 cells. Surprisingly, conjugate5,with Dau at theN-terminus and Lys side chain in position 15, showed the lowest efficacy on the U87 cells. Compound8,with three Dau, showed moderate activity. Thus, the effectiveness of Angiopep-2-daunomycin conjugates does not primarily depend on the number of drug molecules, but rather on their position within the molecule."	"The blood-brain barrier (BBB) is a semipermeable system, and, therefore, most of the active substances are poorly transported through this barrier, resulting in decreased therapeutic effects. Angiopep-2 (TFFYGGSRGKRNNFKTEEY) is a peptide ligand of low-density lipoprotein receptor-related protein-1 (LRP1), which can cross the BBB via receptor-mediated transcytosis and simultaneously target glioblastomas. Angiopep-2 contains three amino groups that have previously been used to produce drug-peptide conjugates, although the role and importance of each position have not yet been investigated. Thus, we studied the number and position of drug molecules in Angiopep-2 based conjugates. Conjugates containing one, two, and three daunomycin molecules conjugated via oxime linkage in all possible variations were prepared. The in vitro cytostatic effect and cellular uptake of the conjugates were investigated on U87 human glioblastoma cells. Degradation studies in the presence of rat liver lysosomal homogenates were also performed in order for us to better understand the structure-activity relationship and to determine the smallest metabolites. Conjugates with the best cytostatic effects had a drug molecule at the N-terminus. We demonstrated that the increasing number of drug molecules does not necessarily increase the efficacy of the conjugates, and proved that modification of the different conjugation sites results in differing biological effectiveness."
REF00250	PDC_00214	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	24.0 &plusmn; 5.9 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U87 cell	.	.	72 h	.	MTT assay	"The in vitro cytostatic effect of the synthesized peptide (1) and daunomycin-peptide conjugates (2-8) was investigated on U87 human glioblastoma cells. The cells were treated with the peptide and conjugates at different concentrations (0.05-50 uM) for 24 h, and after a washing step, the cells were incubated for another 48 h at 37 C. The cytostatic effect of the compounds was determined using the MTT test. The measured IC50values are shown in. The free Angiopep-2 did not show any effect on tumor cells up to a 50 &mu;M concentration. However, no clear correlation could be obtained between the number of the daunomycin and the cytostatic efficacy. Among the conjugates with only one Dau, compound3,in which Dau was attached to theN-terminus, showed the highest in vitro cytostatic effect on glioblastoma cells. When the Dau was conjugated to the Lys side chain in position 15 (compound2), the effect decreased significantly, and conjugate4was also not significantly better. In case of conjugates with two drug molecules, a similar tendency was observed. Compound7,with Dau at theN-terminus and on the Lys side chain in position 10, showed the highest activity. When the Lys side chains were used as conjugation sites, the formed compound (6) had moderate activity on U87 cells. Surprisingly, conjugate5,with Dau at theN-terminus and Lys side chain in position 15, showed the lowest efficacy on the U87 cells. Compound8,with three Dau, showed moderate activity. Thus, the effectiveness of Angiopep-2-daunomycin conjugates does not primarily depend on the number of drug molecules, but rather on their position within the molecule."	"The blood-brain barrier (BBB) is a semipermeable system, and, therefore, most of the active substances are poorly transported through this barrier, resulting in decreased therapeutic effects. Angiopep-2 (TFFYGGSRGKRNNFKTEEY) is a peptide ligand of low-density lipoprotein receptor-related protein-1 (LRP1), which can cross the BBB via receptor-mediated transcytosis and simultaneously target glioblastomas. Angiopep-2 contains three amino groups that have previously been used to produce drug-peptide conjugates, although the role and importance of each position have not yet been investigated. Thus, we studied the number and position of drug molecules in Angiopep-2 based conjugates. Conjugates containing one, two, and three daunomycin molecules conjugated via oxime linkage in all possible variations were prepared. The in vitro cytostatic effect and cellular uptake of the conjugates were investigated on U87 human glioblastoma cells. Degradation studies in the presence of rat liver lysosomal homogenates were also performed in order for us to better understand the structure-activity relationship and to determine the smallest metabolites. Conjugates with the best cytostatic effects had a drug molecule at the N-terminus. We demonstrated that the increasing number of drug molecules does not necessarily increase the efficacy of the conjugates, and proved that modification of the different conjugation sites results in differing biological effectiveness."
REF00250	PDC_00114	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	32.3 &plusmn; 8.1 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U87 cell	.	.	72 h	.	MTT assay	"The in vitro cytostatic effect of the synthesized peptide (1) and daunomycin-peptide conjugates (2-8) was investigated on U87 human glioblastoma cells. The cells were treated with the peptide and conjugates at different concentrations (0.05-50 uM) for 24 h, and after a washing step, the cells were incubated for another 48 h at 37 C. The cytostatic effect of the compounds was determined using the MTT test. The measured IC50values are shown in. The free Angiopep-2 did not show any effect on tumor cells up to a 50 &mu;M concentration. However, no clear correlation could be obtained between the number of the daunomycin and the cytostatic efficacy. Among the conjugates with only one Dau, compound3,in which Dau was attached to theN-terminus, showed the highest in vitro cytostatic effect on glioblastoma cells. When the Dau was conjugated to the Lys side chain in position 15 (compound2), the effect decreased significantly, and conjugate4was also not significantly better. In case of conjugates with two drug molecules, a similar tendency was observed. Compound7,with Dau at theN-terminus and on the Lys side chain in position 10, showed the highest activity. When the Lys side chains were used as conjugation sites, the formed compound (6) had moderate activity on U87 cells. Surprisingly, conjugate5,with Dau at theN-terminus and Lys side chain in position 15, showed the lowest efficacy on the U87 cells. Compound8,with three Dau, showed moderate activity. Thus, the effectiveness of Angiopep-2-daunomycin conjugates does not primarily depend on the number of drug molecules, but rather on their position within the molecule."	"The blood-brain barrier (BBB) is a semipermeable system, and, therefore, most of the active substances are poorly transported through this barrier, resulting in decreased therapeutic effects. Angiopep-2 (TFFYGGSRGKRNNFKTEEY) is a peptide ligand of low-density lipoprotein receptor-related protein-1 (LRP1), which can cross the BBB via receptor-mediated transcytosis and simultaneously target glioblastomas. Angiopep-2 contains three amino groups that have previously been used to produce drug-peptide conjugates, although the role and importance of each position have not yet been investigated. Thus, we studied the number and position of drug molecules in Angiopep-2 based conjugates. Conjugates containing one, two, and three daunomycin molecules conjugated via oxime linkage in all possible variations were prepared. The in vitro cytostatic effect and cellular uptake of the conjugates were investigated on U87 human glioblastoma cells. Degradation studies in the presence of rat liver lysosomal homogenates were also performed in order for us to better understand the structure-activity relationship and to determine the smallest metabolites. Conjugates with the best cytostatic effects had a drug molecule at the N-terminus. We demonstrated that the increasing number of drug molecules does not necessarily increase the efficacy of the conjugates, and proved that modification of the different conjugation sites results in differing biological effectiveness."
REF00250	PDC_00213	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	21.6 &plusmn; 5.4 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U87 cell	.	.	72 h	.	MTT assay	"The in vitro cytostatic effect of the synthesized peptide (1) and daunomycin-peptide conjugates (2-8) was investigated on U87 human glioblastoma cells. The cells were treated with the peptide and conjugates at different concentrations (0.05-50 uM) for 24 h, and after a washing step, the cells were incubated for another 48 h at 37 C. The cytostatic effect of the compounds was determined using the MTT test. The measured IC50values are shown in. The free Angiopep-2 did not show any effect on tumor cells up to a 50 &mu;M concentration. However, no clear correlation could be obtained between the number of the daunomycin and the cytostatic efficacy. Among the conjugates with only one Dau, compound3,in which Dau was attached to theN-terminus, showed the highest in vitro cytostatic effect on glioblastoma cells. When the Dau was conjugated to the Lys side chain in position 15 (compound2), the effect decreased significantly, and conjugate4was also not significantly better. In case of conjugates with two drug molecules, a similar tendency was observed. Compound7,with Dau at theN-terminus and on the Lys side chain in position 10, showed the highest activity. When the Lys side chains were used as conjugation sites, the formed compound (6) had moderate activity on U87 cells. Surprisingly, conjugate5,with Dau at theN-terminus and Lys side chain in position 15, showed the lowest efficacy on the U87 cells. Compound8,with three Dau, showed moderate activity. Thus, the effectiveness of Angiopep-2-daunomycin conjugates does not primarily depend on the number of drug molecules, but rather on their position within the molecule."	"The blood-brain barrier (BBB) is a semipermeable system, and, therefore, most of the active substances are poorly transported through this barrier, resulting in decreased therapeutic effects. Angiopep-2 (TFFYGGSRGKRNNFKTEEY) is a peptide ligand of low-density lipoprotein receptor-related protein-1 (LRP1), which can cross the BBB via receptor-mediated transcytosis and simultaneously target glioblastomas. Angiopep-2 contains three amino groups that have previously been used to produce drug-peptide conjugates, although the role and importance of each position have not yet been investigated. Thus, we studied the number and position of drug molecules in Angiopep-2 based conjugates. Conjugates containing one, two, and three daunomycin molecules conjugated via oxime linkage in all possible variations were prepared. The in vitro cytostatic effect and cellular uptake of the conjugates were investigated on U87 human glioblastoma cells. Degradation studies in the presence of rat liver lysosomal homogenates were also performed in order for us to better understand the structure-activity relationship and to determine the smallest metabolites. Conjugates with the best cytostatic effects had a drug molecule at the N-terminus. We demonstrated that the increasing number of drug molecules does not necessarily increase the efficacy of the conjugates, and proved that modification of the different conjugation sites results in differing biological effectiveness."
REF00250	PDC_00113	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.8 &plusmn; 6.3 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U87 cell	.	.	72 h	.	MTT assay	"The in vitro cytostatic effect of the synthesized peptide (1) and daunomycin-peptide conjugates (2-8) was investigated on U87 human glioblastoma cells. The cells were treated with the peptide and conjugates at different concentrations (0.05-50 uM) for 24 h, and after a washing step, the cells were incubated for another 48 h at 37 C. The cytostatic effect of the compounds was determined using the MTT test. The measured IC50values are shown in. The free Angiopep-2 did not show any effect on tumor cells up to a 50 &mu;M concentration. However, no clear correlation could be obtained between the number of the daunomycin and the cytostatic efficacy. Among the conjugates with only one Dau, compound3,in which Dau was attached to theN-terminus, showed the highest in vitro cytostatic effect on glioblastoma cells. When the Dau was conjugated to the Lys side chain in position 15 (compound2), the effect decreased significantly, and conjugate4was also not significantly better. In case of conjugates with two drug molecules, a similar tendency was observed. Compound7,with Dau at theN-terminus and on the Lys side chain in position 10, showed the highest activity. When the Lys side chains were used as conjugation sites, the formed compound (6) had moderate activity on U87 cells. Surprisingly, conjugate5,with Dau at theN-terminus and Lys side chain in position 15, showed the lowest efficacy on the U87 cells. Compound8,with three Dau, showed moderate activity. Thus, the effectiveness of Angiopep-2-daunomycin conjugates does not primarily depend on the number of drug molecules, but rather on their position within the molecule."	"The blood-brain barrier (BBB) is a semipermeable system, and, therefore, most of the active substances are poorly transported through this barrier, resulting in decreased therapeutic effects. Angiopep-2 (TFFYGGSRGKRNNFKTEEY) is a peptide ligand of low-density lipoprotein receptor-related protein-1 (LRP1), which can cross the BBB via receptor-mediated transcytosis and simultaneously target glioblastomas. Angiopep-2 contains three amino groups that have previously been used to produce drug-peptide conjugates, although the role and importance of each position have not yet been investigated. Thus, we studied the number and position of drug molecules in Angiopep-2 based conjugates. Conjugates containing one, two, and three daunomycin molecules conjugated via oxime linkage in all possible variations were prepared. The in vitro cytostatic effect and cellular uptake of the conjugates were investigated on U87 human glioblastoma cells. Degradation studies in the presence of rat liver lysosomal homogenates were also performed in order for us to better understand the structure-activity relationship and to determine the smallest metabolites. Conjugates with the best cytostatic effects had a drug molecule at the N-terminus. We demonstrated that the increasing number of drug molecules does not necessarily increase the efficacy of the conjugates, and proved that modification of the different conjugation sites results in differing biological effectiveness."
REF00250	PDC_00112	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	23.6 &plusmn; 6.3 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U87 cell	.	.	72 h	.	MTT assay	"The in vitro cytostatic effect of the synthesized peptide (1) and daunomycin-peptide conjugates (2-8) was investigated on U87 human glioblastoma cells. The cells were treated with the peptide and conjugates at different concentrations (0.05-50 uM) for 24 h, and after a washing step, the cells were incubated for another 48 h at 37 C. The cytostatic effect of the compounds was determined using the MTT test. The measured IC50values are shown in. The free Angiopep-2 did not show any effect on tumor cells up to a 50 &mu;M concentration. However, no clear correlation could be obtained between the number of the daunomycin and the cytostatic efficacy. Among the conjugates with only one Dau, compound3,in which Dau was attached to theN-terminus, showed the highest in vitro cytostatic effect on glioblastoma cells. When the Dau was conjugated to the Lys side chain in position 15 (compound2), the effect decreased significantly, and conjugate4was also not significantly better. In case of conjugates with two drug molecules, a similar tendency was observed. Compound7,with Dau at theN-terminus and on the Lys side chain in position 10, showed the highest activity. When the Lys side chains were used as conjugation sites, the formed compound (6) had moderate activity on U87 cells. Surprisingly, conjugate5,with Dau at theN-terminus and Lys side chain in position 15, showed the lowest efficacy on the U87 cells. Compound8,with three Dau, showed moderate activity. Thus, the effectiveness of Angiopep-2-daunomycin conjugates does not primarily depend on the number of drug molecules, but rather on their position within the molecule."	"The blood-brain barrier (BBB) is a semipermeable system, and, therefore, most of the active substances are poorly transported through this barrier, resulting in decreased therapeutic effects. Angiopep-2 (TFFYGGSRGKRNNFKTEEY) is a peptide ligand of low-density lipoprotein receptor-related protein-1 (LRP1), which can cross the BBB via receptor-mediated transcytosis and simultaneously target glioblastomas. Angiopep-2 contains three amino groups that have previously been used to produce drug-peptide conjugates, although the role and importance of each position have not yet been investigated. Thus, we studied the number and position of drug molecules in Angiopep-2 based conjugates. Conjugates containing one, two, and three daunomycin molecules conjugated via oxime linkage in all possible variations were prepared. The in vitro cytostatic effect and cellular uptake of the conjugates were investigated on U87 human glioblastoma cells. Degradation studies in the presence of rat liver lysosomal homogenates were also performed in order for us to better understand the structure-activity relationship and to determine the smallest metabolites. Conjugates with the best cytostatic effects had a drug molecule at the N-terminus. We demonstrated that the increasing number of drug molecules does not necessarily increase the efficacy of the conjugates, and proved that modification of the different conjugation sites results in differing biological effectiveness."
REF00250	PDC_00215	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	16.9 &plusmn; 5.6 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U87 cell	.	.	72 h	.	MTT assay	"The in vitro cytostatic effect and the in vitro cellular uptake of the spacer-containing daunomycin-peptide conjugates (9-11) were studied on U87 human glioblastoma cells as previously described. The measured IC50 values are shown in Table 2, while the measured cellular uptake at 10 &mu;M and 50 &mu;M concentration are given in Figure 4. The fluorescence intensity values showed good correlation with the percentage of daunomycin-positive cells in the case of these conjugates as well. Conjugate 9 showed slight toxicity during the measurements at a concentration of 50 &mu;M."	"The blood-brain barrier (BBB) is a semipermeable system, and, therefore, most of the active substances are poorly transported through this barrier, resulting in decreased therapeutic effects. Angiopep-2 (TFFYGGSRGKRNNFKTEEY) is a peptide ligand of low-density lipoprotein receptor-related protein-1 (LRP1), which can cross the BBB via receptor-mediated transcytosis and simultaneously target glioblastomas. Angiopep-2 contains three amino groups that have previously been used to produce drug-peptide conjugates, although the role and importance of each position have not yet been investigated. Thus, we studied the number and position of drug molecules in Angiopep-2 based conjugates. Conjugates containing one, two, and three daunomycin molecules conjugated via oxime linkage in all possible variations were prepared. The in vitro cytostatic effect and cellular uptake of the conjugates were investigated on U87 human glioblastoma cells. Degradation studies in the presence of rat liver lysosomal homogenates were also performed in order for us to better understand the structure-activity relationship and to determine the smallest metabolites. Conjugates with the best cytostatic effects had a drug molecule at the N-terminus. We demonstrated that the increasing number of drug molecules does not necessarily increase the efficacy of the conjugates, and proved that modification of the different conjugation sites results in differing biological effectiveness."
REF00250	PDC_00216	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U87 cell	.	.	72 h	.	MTT assay	"The in vitro cytostatic effect and the in vitro cellular uptake of the spacer-containing daunomycin-peptide conjugates (9-11) were studied on U87 human glioblastoma cells as previously described. The measured IC50 values are shown in Table 2, while the measured cellular uptake at 10 &mu;M and 50 &mu;M concentration are given in Figure 4. The fluorescence intensity values showed good correlation with the percentage of daunomycin-positive cells in the case of these conjugates as well. Conjugate 9 showed slight toxicity during the measurements at a concentration of 50 &mu;M."	"The blood-brain barrier (BBB) is a semipermeable system, and, therefore, most of the active substances are poorly transported through this barrier, resulting in decreased therapeutic effects. Angiopep-2 (TFFYGGSRGKRNNFKTEEY) is a peptide ligand of low-density lipoprotein receptor-related protein-1 (LRP1), which can cross the BBB via receptor-mediated transcytosis and simultaneously target glioblastomas. Angiopep-2 contains three amino groups that have previously been used to produce drug-peptide conjugates, although the role and importance of each position have not yet been investigated. Thus, we studied the number and position of drug molecules in Angiopep-2 based conjugates. Conjugates containing one, two, and three daunomycin molecules conjugated via oxime linkage in all possible variations were prepared. The in vitro cytostatic effect and cellular uptake of the conjugates were investigated on U87 human glioblastoma cells. Degradation studies in the presence of rat liver lysosomal homogenates were also performed in order for us to better understand the structure-activity relationship and to determine the smallest metabolites. Conjugates with the best cytostatic effects had a drug molecule at the N-terminus. We demonstrated that the increasing number of drug molecules does not necessarily increase the efficacy of the conjugates, and proved that modification of the different conjugation sites results in differing biological effectiveness."
REF00250	PDC_00217	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	20.2 &plusmn; 3.0 &micro;M	&micro;M	.	.	.	.	Glioblastoma	U87 cell	.	.	72 h	.	MTT assay	"The in vitro cytostatic effect and the in vitro cellular uptake of the spacer-containing daunomycin-peptide conjugates (9-11) were studied on U87 human glioblastoma cells as previously described. The measured IC50 values are shown in Table 2, while the measured cellular uptake at 10 &mu;M and 50 &mu;M concentration are given in Figure 4. The fluorescence intensity values showed good correlation with the percentage of daunomycin-positive cells in the case of these conjugates as well. Conjugate 9 showed slight toxicity during the measurements at a concentration of 50 &mu;M."	"The blood-brain barrier (BBB) is a semipermeable system, and, therefore, most of the active substances are poorly transported through this barrier, resulting in decreased therapeutic effects. Angiopep-2 (TFFYGGSRGKRNNFKTEEY) is a peptide ligand of low-density lipoprotein receptor-related protein-1 (LRP1), which can cross the BBB via receptor-mediated transcytosis and simultaneously target glioblastomas. Angiopep-2 contains three amino groups that have previously been used to produce drug-peptide conjugates, although the role and importance of each position have not yet been investigated. Thus, we studied the number and position of drug molecules in Angiopep-2 based conjugates. Conjugates containing one, two, and three daunomycin molecules conjugated via oxime linkage in all possible variations were prepared. The in vitro cytostatic effect and cellular uptake of the conjugates were investigated on U87 human glioblastoma cells. Degradation studies in the presence of rat liver lysosomal homogenates were also performed in order for us to better understand the structure-activity relationship and to determine the smallest metabolites. Conjugates with the best cytostatic effects had a drug molecule at the N-terminus. We demonstrated that the increasing number of drug molecules does not necessarily increase the efficacy of the conjugates, and proved that modification of the different conjugation sites results in differing biological effectiveness."
REF00244	PDC_00219	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.47 &plusmn; 0.54 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00220	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.42 &plusmn; 1.21 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00221	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	25.45 &plusmn; 0.64 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00222	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.12 &plusmn; 0.07 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00223	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.49 &plusmn; 0.58 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00224	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.72 &plusmn; 1.25 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00219	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.29 &plusmn; 0.67 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00220	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.76 &plusmn; 0.79 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00221	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.32 &plusmn; 2.25 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00222	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.78 &plusmn; 0.47 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00223	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.37 &plusmn; 1.18 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00224	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.91 &plusmn; 1.23 &micro;M	&micro;M	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00219	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.29 &plusmn; 1.11 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00220	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.25 &plusmn; 0.96 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00221	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	24.39 &plusmn; 1.45 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00222	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.27 &plusmn; 0.38 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00223	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.12 &plusmn; 0.87 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00224	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	20.35 &plusmn; 1.21 &micro;M	&micro;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00219	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.60 &plusmn; 1.23 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00220	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.93 &plusmn; 1.14 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00221	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	23.09 &plusmn; 1.77 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00222	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.72 &plusmn; 0.92 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00223	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11.51 &plusmn; 1.37 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00224	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	28.24 &plusmn; 1.36 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00219	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	23.90 &plusmn; 1.58 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00220	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	20.41 &plusmn; 1.04 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00221	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	35.20 &plusmn; 2.64 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00222	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	17.14 &plusmn; 2.42 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00223	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	18.25 &plusmn; 1.76 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00244	PDC_00224	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	25.16 &plusmn; 2.12 &micro;M	&micro;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	MTT assay	"The cytotoxicity of conjugates was evaluated on cell lines with different expression levels of HER2. The results showed that among all conjugates with a single CPT molecule (I-1 to I-3), I-1 was the most cytotoxic against three HER2-positive cell lines (SK-BR-3, NCI-N87, and SK-OV-3 cells), and the calculated IC50 values for the three cells were 1.47 &plusmn; 0.54, 3.29 &plusmn; 0.67, and 4.29 &plusmn; 1.11 uM, respectively. Similarly, among all conjugates with two CPT molecules (I-4 to I-6), I-4 showed the highest cytotoxicity toward HER2-positive cells, and the IC50 values for SK-BR-3, NCI-N87, and SK-OV-3 cells were 0.12 &plusmn; 0.07, 1.78 &plusmn; 0.47, and 1.27 &plusmn; 0.38 uM, respectively. The activity of I-4 against SK-BR-3 cells was also slightly better than that of the positive control CPT (IC50 = 0.21 &plusmn; 0.04 uM). The cytotoxicity of I-1 and I-4 against HER2-negative MDA-MB-231 cells was comparatively lower (calculated IC50s were 7.60 &plusmn; 1.23 and 7.72 &plusmn; 0.92 uM, respectively). In contrast, CPT itself showed higher cytotoxicity against MDA-MB-231 (IC50 = 1.06 &plusmn; 0.42 uM), indicating that conjugates showed higher specificity in cell targeting. Furthermore, the cytotoxicity of I-1 and I-4 against normal cells MCF-10A (IC50 = 23.90 &plusmn; 1.58 and 17.14 &plusmn; 2.42 uM, respectively) was significantly lower than that of CPT alone (2.58 &plusmn; 0.77 uM). Based on these results, I-1 and I-4 were selected for subsequent biological evaluation."	"To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptidesP1GCGT1andP1GCGCGT1were designed using anin silicoapproach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain,P1GCGT1andP1GCGCGT1could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among whichI-1andI-4were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated thatI-1andI-4induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed thatI-1andI-4were effective at targeting HER2. Moreover,I-1andI-4showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice."
REF00240	PDC_00136	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	15.34 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	24 h	.	.	"First, we probed the novel PDCs in non-cancerous human foreskin fibroblasts (HFF-1 cells). After 24 h treatment with different concentrations of PDCs, HFF-1 cells were still viable, while after adding doxorubicin viability was decreased up to 72%. In comparison, when we elucidated PDC activity in HeLa cells and exposed them for 24 h to various concentrations of the conjugates (2.5-70 &mu;M), all of the PDCs, as well as free Dox, exhibited EC50 values in the lower micromolar range (PDC-1: 15.34 &mu;M, PDC-2: 14.47 &mu;M, PDC-3: 27.01 &mu;M, Dox: 6.78 &mu;M data not shown). The higher activity compared to HFF cells might be attributed to the fact that the PDCs were internalized to far less of an extent into the non-cancerous cell line. This observation might be advantageous and could reflect some selectivity of the more basic and positively charged peptides towards cancerous cells. We also noted that the obtained EC50 values somehow agreed with the results of the former assays. For example, sC18E was taken up to a significantly higher extent compared to sC18* and should, therefore, exhibit higher activity, e.g., drug delivery. However, surprisingly, the EC50 values of the PDCs containing sC18 and sC18E were quite similar, although sC18E significantly outcompeted sC18 in internalization activity."	"Herein, the design and synthesis of peptide-drug conjugates (PDCs) including different variants of the cell-penetrating peptide sC18 is presented. We first generated a series of novel sequence mutants of sC18 having either amino acid deletions and/or substitutions, and then tested their biological activity. The effects of histidine substituents were found to be not meaningful for sC18 uptake and cell selectivity. Moreover, building a nearly perfect amphipathic structure within a shortened sC18 derivative provided a peptide that was highly membrane-active, but also too cytotoxic. As a result, the most promising analog was sC18E, which stands out due to its higher uptake efficacy compared to parent sC18. In the last set of experiments, we let the peptides react with the cytotoxic drug doxorubicin by Thiol-Michael addition to form novel PDCs. Our results indicate that sC18&delta;E could be a more efficient drug carrier than parent sC18 for biomedical applications. However, cellular uptake using endocytosis and resulting entrapment of cargo inside vesicles is still a major critical step to overcome in CPP-containing peptide-drug development."
REF00240	PDC_00137	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	14.47 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	24 h	.	.	"First, we probed the novel PDCs in non-cancerous human foreskin fibroblasts (HFF-1 cells). After 24 h treatment with different concentrations of PDCs, HFF-1 cells were still viable, while after adding doxorubicin viability was decreased up to 72%. In comparison, when we elucidated PDC activity in HeLa cells and exposed them for 24 h to various concentrations of the conjugates (2.5-70 &mu;M), all of the PDCs, as well as free Dox, exhibited EC50 values in the lower micromolar range (PDC-1: 15.34 &mu;M, PDC-2: 14.47 &mu;M, PDC-3: 27.01 &mu;M, Dox: 6.78 &mu;M data not shown). The higher activity compared to HFF cells might be attributed to the fact that the PDCs were internalized to far less of an extent into the non-cancerous cell line. This observation might be advantageous and could reflect some selectivity of the more basic and positively charged peptides towards cancerous cells. We also noted that the obtained EC50 values somehow agreed with the results of the former assays. For example, sC18E was taken up to a significantly higher extent compared to sC18* and should, therefore, exhibit higher activity, e.g., drug delivery. However, surprisingly, the EC50 values of the PDCs containing sC18 and sC18E were quite similar, although sC18E significantly outcompeted sC18 in internalization activity."	"Herein, the design and synthesis of peptide-drug conjugates (PDCs) including different variants of the cell-penetrating peptide sC18 is presented. We first generated a series of novel sequence mutants of sC18 having either amino acid deletions and/or substitutions, and then tested their biological activity. The effects of histidine substituents were found to be not meaningful for sC18 uptake and cell selectivity. Moreover, building a nearly perfect amphipathic structure within a shortened sC18 derivative provided a peptide that was highly membrane-active, but also too cytotoxic. As a result, the most promising analog was sC18E, which stands out due to its higher uptake efficacy compared to parent sC18. In the last set of experiments, we let the peptides react with the cytotoxic drug doxorubicin by Thiol-Michael addition to form novel PDCs. Our results indicate that sC18E could be a more efficient drug carrier than parent sC18 for biomedical applications. However, cellular uptake using endocytosis and resulting entrapment of cargo inside vesicles is still a major critical step to overcome in CPP-containing peptide-drug development."
REF00240	PDC_00135	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	27.01 &micro;M	&mu;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	24 h	.	.	"First, we probed the novel PDCs in non-cancerous human foreskin fibroblasts (HFF-1 cells). After 24 h treatment with different concentrations of PDCs, HFF-1 cells were still viable, while after adding doxorubicin viability was decreased up to 72%. In comparison, when we elucidated PDC activity in HeLa cells and exposed them for 24 h to various concentrations of the conjugates (2.5-70 &mu;M), all of the PDCs, as well as free Dox, exhibited EC50 values in the lower micromolar range (PDC-1: 15.34 &mu;M, PDC-2: 14.47 &mu;M, PDC-3: 27.01 &mu;M, Dox: 6.78 &mu;M data not shown). The higher activity compared to HFF cells might be attributed to the fact that the PDCs were internalized to far less of an extent into the non-cancerous cell line. This observation might be advantageous and could reflect some selectivity of the more basic and positively charged peptides towards cancerous cells. We also noted that the obtained EC50 values somehow agreed with the results of the former assays. For example, sC18E was taken up to a significantly higher extent compared to sC18* and should, therefore, exhibit higher activity, e.g., drug delivery. However, surprisingly, the EC50 values of the PDCs containing sC18 and sC18E were quite similar, although sC18E significantly outcompeted sC18 in internalization activity."	"Herein, the design and synthesis of peptide-drug conjugates (PDCs) including different variants of the cell-penetrating peptide sC18 is presented. We first generated a series of novel sequence mutants of sC18 having either amino acid deletions and/or substitutions, and then tested their biological activity. The effects of histidine substituents were found to be not meaningful for sC18 uptake and cell selectivity. Moreover, building a nearly perfect amphipathic structure within a shortened sC18 derivative provided a peptide that was highly membrane-active, but also too cytotoxic. As a result, the most promising analog was sC18E, which stands out due to its higher uptake efficacy compared to parent sC18. In the last set of experiments, we let the peptides react with the cytotoxic drug doxorubicin by Thiol-Michael addition to form novel PDCs. Our results indicate that sC18E could be a more efficient drug carrier than parent sC18 for biomedical applications. However, cellular uptake using endocytosis and resulting entrapment of cargo inside vesicles is still a major critical step to overcome in CPP-containing peptide-drug development."
REF00238	PDC_00152	Ovarianteratoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	10 &micro;M	&micro;M	.	.	.	.	Ovarian mixed germ cell tumor	PA-1 cell	.	.	2 h	.	Annexin V: FITC Apoptosis Detection Kit I (BD Pharmingen)	"Having demonstrated that FU-NHOH successfully delivered AS1411 to the cancer cell nucleus, we then tested their anticancer effect on different cells. We chose 20 uM (N/P 72) FU-NHOH for AS1411 delivery in PA-1 cells as this ratio was confirmed to be successfully assembled with AS1411 and had good transfection efficiency. AS1411, 20 uM FU-NHOH alone or assembled with scrambled DNA (FU-NHOH/NC) had a weak anticancer effect on the PA-1 cells, while when 20 uM FU-NHOH was assembled with AS1411, the anticancer effect was significantly increased. In addition, we found that the IC50of FU-NHOH-AS1411 particles was approximately 10 uM in the PA-1 cells (shown in Fig. S10), while the IC50of FU-NHOH was approximately 40 uM, indicating the synergistic effect of the combination therapy. The positive control Oligofectamine/AS1411 showed better cell toxicity than Oligofectamine alone, indicating the cellular toxicity of AS1411. We also tested the anticancer effect of FU-NHOH/AS1411 nanoparticles on Huh 7 cells or HT-29 cells,we chose 80 uM (N/P 288) FU-NHOH for AS1411 delivery considering its transfection efficiency and peptide toxicity in these two cell lines. Similar to PA-1 cells, FU-NHOH/AS1411 nanoparticles showed a synergistic effect of the combination therapy as the IC50of FU-NHOH was approximately 120 uM and 90 uM in Huh-7 cells and HT-29 cells, whereas, the IC50of FU-NHOH-AS1411 nanoparticles in those cells were approximately 80 uM and 50 uM, respectively. The anticancer effect in PA-1 cells was much stronger than that in the other two cancer cell lines partly because the cancer stem-like PA-1 cells were more sensitive to this combination therapy. The negligible toxicity toward normal 293T cells suggested that our delivery system had low toxicity, which may have good potential for clinical application."	.
REF00238	PDC_00152	Liver cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	80 &micro;M	&micro;M	.	.	.	.	Hepatocellular carcinoma	Huh-7 cell	.	.	2 h	.	Annexin V: FITC Apoptosis Detection Kit I (BD Pharmingen)	"Having demonstrated that FU-NHOH successfully delivered AS1411 to the cancer cell nucleus, we then tested their anticancer effect on different cells. We chose 20 uM (N/P 72) FU-NHOH for AS1411 delivery in PA-1 cells as this ratio was confirmed to be successfully assembled with AS1411 and had good transfection efficiency. AS1411, 20 uM FU-NHOH alone or assembled with scrambled DNA (FU-NHOH/NC) had a weak anticancer effect on the PA-1 cells, while when 20 uM FU-NHOH was assembled with AS1411, the anticancer effect was significantly increased. In addition, we found that the IC50of FU-NHOH-AS1411 particles was approximately 10 uM in the PA-1 cells (shown in Fig. S10), while the IC50of FU-NHOH was approximately 40 uM, indicating the synergistic effect of the combination therapy. The positive control Oligofectamine/AS1411 showed better cell toxicity than Oligofectamine alone, indicating the cellular toxicity of AS1411. We also tested the anticancer effect of FU-NHOH/AS1411 nanoparticles on Huh 7 cells or HT-29 cells,we chose 80 uM (N/P 288) FU-NHOH for AS1411 delivery considering its transfection efficiency and peptide toxicity in these two cell lines. Similar to PA-1 cells, FU-NHOH/AS1411 nanoparticles showed a synergistic effect of the combination therapy as the IC50of FU-NHOH was approximately 120 uM and 90 uM in Huh-7 cells and HT-29 cells, whereas, the IC50of FU-NHOH-AS1411 nanoparticles in those cells were approximately 80 uM and 50 uM, respectively. The anticancer effect in PA-1 cells was much stronger than that in the other two cancer cell lines partly because the cancer stem-like PA-1 cells were more sensitive to this combination therapy. The negligible toxicity toward normal 293T cells suggested that our delivery system had low toxicity, which may have good potential for clinical application."	.
REF00238	PDC_00152	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Colon cancer	HT29 cell	.	.	2 h	.	Annexin V: FITC Apoptosis Detection Kit I (BD Pharmingen)	"Having demonstrated that FU-NHOH successfully delivered AS1411 to the cancer cell nucleus, we then tested their anticancer effect on different cells. We chose 20 uM (N/P 72) FU-NHOH for AS1411 delivery in PA-1 cells as this ratio was confirmed to be successfully assembled with AS1411 and had good transfection efficiency. AS1411, 20 uM FU-NHOH alone or assembled with scrambled DNA (FU-NHOH/NC) had a weak anticancer effect on the PA-1 cells, while when 20 uM FU-NHOH was assembled with AS1411, the anticancer effect was significantly increased. In addition, we found that the IC50of FU-NHOH-AS1411 particles was approximately 10 uM in the PA-1 cells (shown in Fig. S10), while the IC50of FU-NHOH was approximately 40 uM, indicating the synergistic effect of the combination therapy. The positive control Oligofectamine/AS1411 showed better cell toxicity than Oligofectamine alone, indicating the cellular toxicity of AS1411. We also tested the anticancer effect of FU-NHOH/AS1411 nanoparticles on Huh 7 cells or HT-29 cells,we chose 80 uM (N/P 288) FU-NHOH for AS1411 delivery considering its transfection efficiency and peptide toxicity in these two cell lines. Similar to PA-1 cells, FU-NHOH/AS1411 nanoparticles showed a synergistic effect of the combination therapy as the IC50of FU-NHOH was approximately 120 uM and 90 uM in Huh-7 cells and HT-29 cells, whereas, the IC50of FU-NHOH-AS1411 nanoparticles in those cells were approximately 80 uM and 50 uM, respectively. The anticancer effect in PA-1 cells was much stronger than that in the other two cancer cell lines partly because the cancer stem-like PA-1 cells were more sensitive to this combination therapy. The negligible toxicity toward normal 293T cells suggested that our delivery system had low toxicity, which may have good potential for clinical application."	.
REF00236	PDC_00069	Breast cancer	MDA-MB-468 cell-derived xenograft (CDX) model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	81%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	21 days	3 mg/kg qw	.	"The efficacy of BT8009 was evaluated in a cell-derived xenograft (CDX) model using breast adenocarcinoma (MDA-MB-468) cells, which express Nectin-4.When tested at a dose of 3 mg/kg once weekly, significant antitumor activity was observed. At a dose of 3 mg/kg twice weekly or 5 mg/kg once weekly, potent efficacy was achieved with almost complete regression of the tumor after 18 days. Importantly, following cessation of dosing after 18 days, animals from the 5 mg/kg once weekly dosing group were monitored up to day 42, and no tumor regrowth was observed. Consistent animal body weights throughout the study indicate that BT8009 appeared to be well-tolerated at all doses tested. In additional studies reported elsewhere, BT8009 has shown preclinical efficacy in a wide range of CDX and PDX tumor types with full tumor regression seen in small and large tumors, where efficacy broadly correlates with Nectin-4 expression. Additionally, when BT8009 was codosed with an excess of an MMAE-free analogue, efficacy was attenuated, and a BTC incorporating a nonbinding Bicycle analogue showed a demonstrably lower rate and degree of tumor regression. "	"Nectin-4 is a cell adhesion molecule from the Nectin and Nectin-like family. It is a clinically validated tumor target and has been reported to be highly expressed in a wide range of solid tumors, including bladder, esophageal, pancreatic, and lung, but with limited distribution in healthy tissues.An antibody drug conjugate (PADCEV, enfortumab vedotin) that targets Nectin-4 was recently approved for the treatment of bladder cancer following the generation of positive data in a number of clinical studies. Herein we describe the discovery via phage display and subsequent chemical optimization of a Nectin-4 binding Bicycle and its incorporation into BT8009, a BTC that is currently under clinical evaluation. A detailed report of the pharmacologic properties of BT8009 has recently been described.In this, BT8009 shows potent efficacy in multiple tumor models, including patient-derived xenografts, across a variety of tumor indications and is well-tolerated in preclinical safety studies. In several models it demonstrated superior or equivalent efficacy to an analogue of the ADC PADCEV."
REF00236	PDC_00069	Breast cancer	MDA-MB-468 cell-derived xenograft (CDX) model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	93%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	21 days	3 mg/kg biw	.	"The efficacy of BT8009 was evaluated in a cell-derived xenograft (CDX) model using breast adenocarcinoma (MDA-MB-468) cells, which express Nectin-4.When tested at a dose of 3 mg/kg once weekly, significant antitumor activity was observed. At a dose of 3 mg/kg twice weekly or 5 mg/kg once weekly, potent efficacy was achieved with almost complete regression of the tumor after 18 days. Importantly, following cessation of dosing after 18 days, animals from the 5 mg/kg once weekly dosing group were monitored up to day 42, and no tumor regrowth was observed. Consistent animal body weights throughout the study indicate that BT8009 appeared to be well-tolerated at all doses tested. In additional studies reported elsewhere, BT8009 has shown preclinical efficacy in a wide range of CDX and PDX tumor types with full tumor regression seen in small and large tumors, where efficacy broadly correlates with Nectin-4 expression. Additionally, when BT8009 was codosed with an excess of an MMAE-free analogue, efficacy was attenuated, and a BTC incorporating a nonbinding Bicycle analogue showed a demonstrably lower rate and degree of tumor regression. "	"Nectin-4 is a cell adhesion molecule from the Nectin and Nectin-like family. It is a clinically validated tumor target and has been reported to be highly expressed in a wide range of solid tumors, including bladder, esophageal, pancreatic, and lung, but with limited distribution in healthy tissues.An antibody drug conjugate (PADCEV, enfortumab vedotin) that targets Nectin-4 was recently approved for the treatment of bladder cancer following the generation of positive data in a number of clinical studies. Herein we describe the discovery via phage display and subsequent chemical optimization of a Nectin-4 binding Bicycle and its incorporation into BT8009, a BTC that is currently under clinical evaluation. A detailed report of the pharmacologic properties of BT8009 has recently been described.In this, BT8009 shows potent efficacy in multiple tumor models, including patient-derived xenografts, across a variety of tumor indications and is well-tolerated in preclinical safety studies. In several models it demonstrated superior or equivalent efficacy to an analogue of the ADC PADCEV."
REF00236	PDC_00069	Breast cancer	MDA-MB-468 cell-derived xenograft (CDX) model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	93%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	21 days	5 mg/kg qw	.	"The efficacy of BT8009 was evaluated in a cell-derived xenograft (CDX) model using breast adenocarcinoma (MDA-MB-468) cells, which express Nectin-4.When tested at a dose of 3 mg/kg once weekly, significant antitumor activity was observed. At a dose of 3 mg/kg twice weekly or 5 mg/kg once weekly, potent efficacy was achieved with almost complete regression of the tumor after 18 days. Importantly, following cessation of dosing after 18 days, animals from the 5 mg/kg once weekly dosing group were monitored up to day 42, and no tumor regrowth was observed. Consistent animal body weights throughout the study indicate that BT8009 appeared to be well-tolerated at all doses tested. In additional studies reported elsewhere, BT8009 has shown preclinical efficacy in a wide range of CDX and PDX tumor types with full tumor regression seen in small and large tumors, where efficacy broadly correlates with Nectin-4 expression. Additionally, when BT8009 was codosed with an excess of an MMAE-free analogue, efficacy was attenuated, and a BTC incorporating a nonbinding Bicycle analogue showed a demonstrably lower rate and degree of tumor regression. "	"Nectin-4 is a cell adhesion molecule from the Nectin and Nectin-like family. It is a clinically validated tumor target and has been reported to be highly expressed in a wide range of solid tumors, including bladder, esophageal, pancreatic, and lung, but with limited distribution in healthy tissues.An antibody drug conjugate (PADCEV, enfortumab vedotin) that targets Nectin-4 was recently approved for the treatment of bladder cancer following the generation of positive data in a number of clinical studies. Herein we describe the discovery via phage display and subsequent chemical optimization of a Nectin-4 binding Bicycle and its incorporation into BT8009, a BTC that is currently under clinical evaluation. A detailed report of the pharmacologic properties of BT8009 has recently been described.In this, BT8009 shows potent efficacy in multiple tumor models, including patient-derived xenografts, across a variety of tumor indications and is well-tolerated in preclinical safety studies. In several models it demonstrated superior or equivalent efficacy to an analogue of the ADC PADCEV."
REF00235	PDC_00321	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Apoptosis rate	60%	%	.	.	.	.	Hepatocellular carcinoma	Huh-7 cell	.	.	.	10 &micro;M	.	"The improved proapoptotic activity of QR-KLU was further confirmed by Annexin V-PI staining through FACS. Viable cells, early apoptotic cells, necrotic cells, late apoptotic cells were represented by Q4, Q3, Q2 and Q1 respectively. Peptide QR-KLU displayed a significant proapoptotic effect under 10 uM with apoptosis rate over 60% in Huh 7 cells and over 40% in HUVEC cells."	"In this paper, we designed a novel PDC which was a conjugation of VEGFR targeting peptide VEGF125-136 and a lytic peptide. This novel peptide conjugate may not only target VEGFR expressed on endothelial cells and inhibit angiogenesis, but also potently inhibit cancer cell proliferation through destroying cell membrane. As its different mechanism from chemotherapeutics, this PDC has a good potential for chemo-resistance cancer therapy. We recognized this peptide could be a potential drug candidate delivered through TAE for HCC therapy. As we know, there has not been a peptide inhibitor used in combination with TACE for HCC therapy. So we developed a VX2 rabbit tumor model and applied this peptide conjugate to TAE for liver cancer therapy, in which this peptide demonstrated better in vivo anti-tumor and anti-angiogenesis effect than conventional TACE. This work may provide an alternative option in combination with TACE for HCC therapy in the future."
REF00235	PDC_00321	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Apoptosis rate	40%	%	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	.	.	10 &micro;M	.	"The improved proapoptotic activity of QR-KLU was further confirmed by Annexin V-PI staining through FACS. Viable cells, early apoptotic cells, necrotic cells, late apoptotic cells were represented by Q4, Q3, Q2 and Q1 respectively. Peptide QR-KLU displayed a significant proapoptotic effect under 10 uM with apoptosis rate over 60% in Huh 7 cells and over 40% in HUVEC cells."	"In this paper, we designed a novel PDC which was a conjugation of VEGFR targeting peptide VEGF125-136 and a lytic peptide. This novel peptide conjugate may not only target VEGFR expressed on endothelial cells and inhibit angiogenesis, but also potently inhibit cancer cell proliferation through destroying cell membrane. As its different mechanism from chemotherapeutics, this PDC has a good potential for chemo-resistance cancer therapy. We recognized this peptide could be a potential drug candidate delivered through TAE for HCC therapy. As we know, there has not been a peptide inhibitor used in combination with TACE for HCC therapy. So we developed a VX2 rabbit tumor model and applied this peptide conjugate to TAE for liver cancer therapy, in which this peptide demonstrated better in vivo anti-tumor and anti-angiogenesis effect than conventional TACE. This work may provide an alternative option in combination with TACE for HCC therapy in the future."
REF00235	PDC_00321	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.3 &plusmn; 0.74 &micro;M	&micro;M	.	.	.	.	Hepatocellular carcinoma	Huh-7 cell	.	.	48 h	.	CCK8 assay	"The effect of the peptide conjugate QR-KLU on the proliferation of Huh7 and HUVEC cells was assessed by CCK8 assays. First, we investigated anti-proliferation ability of three peptides QR, KLU and QR-KLU on Huh7 and HUVEC cells with different concentrations. As shown in Fig. Fig.3A,3A, B, cells were treated with QR peptide, KLU peptide, QR-KLU peptide, DOX with different concentration respectively. The inhibition rate increased in a dose-dependent manner in KLU and QR-KLU groups in both cell lines. In HUVEC cells, peptide QR-KLU (IC50 10.7 &plusmn; 0.292 uM) showed more potent inhibition effect than KLU (IC50 33.8 &plusmn; 0.98 uM), and in Huh7 cells, QR-KLU (IC50 7.3 &plusmn; 0.74 uM) also showed more potent anti-tumor effect than KLU (IC50 36.27 &plusmn; 2.7 uM). Meanwhile, peptide QR showed negligible toxicity even under 80 uM."	"In this paper, we designed a novel PDC which was a conjugation of VEGFR targeting peptide VEGF125-136 and a lytic peptide. This novel peptide conjugate may not only target VEGFR expressed on endothelial cells and inhibit angiogenesis, but also potently inhibit cancer cell proliferation through destroying cell membrane. As its different mechanism from chemotherapeutics, this PDC has a good potential for chemo-resistance cancer therapy. We recognized this peptide could be a potential drug candidate delivered through TAE for HCC therapy. As we know, there has not been a peptide inhibitor used in combination with TACE for HCC therapy. So we developed a VX2 rabbit tumor model and applied this peptide conjugate to TAE for liver cancer therapy, in which this peptide demonstrated better in vivo anti-tumor and anti-angiogenesis effect than conventional TACE. This work may provide an alternative option in combination with TACE for HCC therapy in the future."
REF00235	PDC_00321	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.7 &plusmn; 0.292 &micro;M	&micro;M	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	.	48 h	.	CCK8 assay	"The effect of the peptide conjugate QR-KLU on the proliferation of Huh7 and HUVEC cells was assessed by CCK8 assays. First, we investigated anti-proliferation ability of three peptides QR, KLU and QR-KLU on Huh7 and HUVEC cells with different concentrations. As shown in Fig. Fig.3A,3A, B, cells were treated with QR peptide, KLU peptide, QR-KLU peptide, DOX with different concentration respectively. The inhibition rate increased in a dose-dependent manner in KLU and QR-KLU groups in both cell lines. In HUVEC cells, peptide QR-KLU (IC50 10.7 &plusmn; 0.292 uM) showed more potent inhibition effect than KLU (IC50 33.8 &plusmn; 0.98 uM), and in Huh7 cells, QR-KLU (IC50 7.3 &plusmn; 0.74 uM) also showed more potent anti-tumor effect than KLU (IC50 36.27 &plusmn; 2.7 uM). Meanwhile, peptide QR showed negligible toxicity even under 80 uM."	"In this paper, we designed a novel PDC which was a conjugation of VEGFR targeting peptide VEGF125-136 and a lytic peptide. This novel peptide conjugate may not only target VEGFR expressed on endothelial cells and inhibit angiogenesis, but also potently inhibit cancer cell proliferation through destroying cell membrane. As its different mechanism from chemotherapeutics, this PDC has a good potential for chemo-resistance cancer therapy. We recognized this peptide could be a potential drug candidate delivered through TAE for HCC therapy. As we know, there has not been a peptide inhibitor used in combination with TACE for HCC therapy. So we developed a VX2 rabbit tumor model and applied this peptide conjugate to TAE for liver cancer therapy, in which this peptide demonstrated better in vivo anti-tumor and anti-angiogenesis effect than conventional TACE. This work may provide an alternative option in combination with TACE for HCC therapy in the future."
REF00234	PDC_00349	Melanoma	Nude mice hTNBCSC cells xenograft tumor model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	30%	%	.	.	.	.	Triple-negative breast cancer	Human triple-negative breast cancer stem cell (hTNBCSC)	.	.	20 days	8.75 mg/kg	.	"In vivo assessment in tumor-bearing animal models classically complements cell cultures data for comparing cancer treatment efficacies. For this reason, hTNBCSC and hOvCSC xenografts were implanted subcutaneously into immunodeficient mice as described in the Methods section with only 1000 cells given their highly tumorigenic nature. Three days later, the animals began receiving weekly IV bolus administration of either vehicle, docetaxel, or TH1902. Docetaxel was administered at a dose (15 mg/kg/week; for 3 cycles) in accordance with the estimated maximal tolerated dose (MTD) for mice, as well as at 1/4 of the MTD (3.75 mg/kg/week). TH1902 was administered at doses (35 and 8.75 mg/kg/week) which contained quantities of docetaxel equivalent to those in the two administrations of free docetaxel. From the size of the hTNBCSC and hOvCSC tumors, it is apparent that docetaxel had little impact on xenografts growth when administered neither at its MTD, for both hTNBCSC and hOvCSC, nor at 1/4 of this dosage as reflected by the growth curves. TH1902, when administered at a dosage equivalent to docetaxel at its MTD, provided greater tumor growth inhibition than did docetaxel for both xenograft models. Furthermore, higher dosage of administered TH1902 (up to 1.5 equivalent of docetaxel MTD) did not generate significant differences in terms of hOvCSC tumor inhibition without affecting mice body weights suggesting that TH1902, even at higher doses, is better tolerated compared to docetaxel. Then, in order to statistically compare the effects of docetaxel and TH1902 on tumor growth, the tumor sizes measured at the vehicle group endpoint were compared and statistically significant differences between the tumor sizes in vehicle-treated animals found in TH1902-treated animals for hTNBCSC and hOvCSC. Mouse body weight was used as an indicator of the morbidity associated with administration of docetaxel or TH1902. Administration of docetaxel at its MTD provoked a weight loss that approached 10% after the treatments, which is often observed in xenograft models with administration of docetaxel at this level. The body weights of animals treated with an equivalent quantity or a 1.5-fold equivalent of TH1902 were maintained at a roughly constant level throughout the experiment. The animals treated with vehicle recorded a slight weight gain (~5%) over this period while animals treated with the lower dosages of docetaxel or TH1902 were similar to the animals treated with vehicle. The body weight data indicates that TH1902 appears to be better tolerated than the equivalent quantity of free docetaxel, in addition to the fact that TH1902 is more efficacious than docetaxel when administered in vivo in the murine models of CSC tested."	"Sortilin (SORT1) is a receptor protein which cycles from the cell surface through intracellular membrane bodies. It binds several circulating proteins and peptides, including progranulin and neurotensin, prior to their rapid intracellular internalization. It is also involved in their intracellular trafficking in endosomal vesicles from the plasma membrane to lysosomes through the endocytic pathway. Deregulation in SORT1 functions has been implicated in cardiovascular disease, Alzheimers disease, and diabetes, whereas its upregulation has been documented in several forms of cancer. Recently, TH1902, a peptide-drug conjugate (PDC) to which two docetaxel molecules were linked to TH19P01 peptide, was generated. TH1902 was demonstrated to recognize and exploit SORT1 functions, and to efficiently inhibit in vitro cell proliferation, and in vivo growth of xenografts from gynecological cancers including triple-negative breast cancer (TNBC)-derived MDA-MB-231 cells, ovarian cancer-derived ES2 and SKOV3 cells, as well as endometrial cancer-derived AN3-CA cells. Interestingly, TH1902 was found to reduce in vitro vasculogenic mimicry (VM) processes in breast and ovarian cancer cells. While some molecular aspects revealing the inter-relationship existence between CSC and VM have been addressed in breast cancer, gastrointestinal cancer, and melanoma, the specific targeting of the CSC subpopulation by TH1902 remains unexplored."
REF00234	PDC_00349	Melanoma	Nude mice hTNBCSC cells xenograft tumor model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	75%	%	.	.	.	.	Triple-negative breast cancer	Human triple-negative breast cancer stem cell (hTNBCSC)	.	.	20 days	35 mg/kg	.	"In vivo assessment in tumor-bearing animal models classically complements cell cultures data for comparing cancer treatment efficacies. For this reason, hTNBCSC and hOvCSC xenografts were implanted subcutaneously into immunodeficient mice as described in the Methods section with only 1000 cells given their highly tumorigenic nature. Three days later, the animals began receiving weekly IV bolus administration of either vehicle, docetaxel, or TH1902. Docetaxel was administered at a dose (15 mg/kg/week; for 3 cycles) in accordance with the estimated maximal tolerated dose (MTD) for mice, as well as at 1/4 of the MTD (3.75 mg/kg/week). TH1902 was administered at doses (35 and 8.75 mg/kg/week) which contained quantities of docetaxel equivalent to those in the two administrations of free docetaxel. From the size of the hTNBCSC and hOvCSC tumors, it is apparent that docetaxel had little impact on xenografts growth when administered neither at its MTD, for both hTNBCSC and hOvCSC, nor at 1/4 of this dosage as reflected by the growth curves. TH1902, when administered at a dosage equivalent to docetaxel at its MTD, provided greater tumor growth inhibition than did docetaxel for both xenograft models. Furthermore, higher dosage of administered TH1902 (up to 1.5 equivalent of docetaxel MTD) did not generate significant differences in terms of hOvCSC tumor inhibition without affecting mice body weights suggesting that TH1902, even at higher doses, is better tolerated compared to docetaxel. Then, in order to statistically compare the effects of docetaxel and TH1902 on tumor growth, the tumor sizes measured at the vehicle group endpoint were compared and statistically significant differences between the tumor sizes in vehicle-treated animals found in TH1902-treated animals for hTNBCSC and hOvCSC. Mouse body weight was used as an indicator of the morbidity associated with administration of docetaxel or TH1902. Administration of docetaxel at its MTD provoked a weight loss that approached 10% after the treatments, which is often observed in xenograft models with administration of docetaxel at this level. The body weights of animals treated with an equivalent quantity or a 1.5-fold equivalent of TH1902 were maintained at a roughly constant level throughout the experiment. The animals treated with vehicle recorded a slight weight gain (~5%) over this period while animals treated with the lower dosages of docetaxel or TH1902 were similar to the animals treated with vehicle. The body weight data indicates that TH1902 appears to be better tolerated than the equivalent quantity of free docetaxel, in addition to the fact that TH1902 is more efficacious than docetaxel when administered in vivo in the murine models of CSC tested."	"Sortilin (SORT1) is a receptor protein which cycles from the cell surface through intracellular membrane bodies. It binds several circulating proteins and peptides, including progranulin and neurotensin, prior to their rapid intracellular internalization. It is also involved in their intracellular trafficking in endosomal vesicles from the plasma membrane to lysosomes through the endocytic pathway. Deregulation in SORT1 functions has been implicated in cardiovascular disease, Alzheimers disease, and diabetes, whereas its upregulation has been documented in several forms of cancer. Recently, TH1902, a peptide-drug conjugate (PDC) to which two docetaxel molecules were linked to TH19P01 peptide, was generated. TH1902 was demonstrated to recognize and exploit SORT1 functions, and to efficiently inhibit in vitro cell proliferation, and in vivo growth of xenografts from gynecological cancers including triple-negative breast cancer (TNBC)-derived MDA-MB-231 cells, ovarian cancer-derived ES2 and SKOV3 cells, as well as endometrial cancer-derived AN3-CA cells. Interestingly, TH1902 was found to reduce in vitro vasculogenic mimicry (VM) processes in breast and ovarian cancer cells. While some molecular aspects revealing the inter-relationship existence between CSC and VM have been addressed in breast cancer, gastrointestinal cancer, and melanoma, the specific targeting of the CSC subpopulation by TH1902 remains unexplored."
REF00234	PDC_00349	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	78.60%	%	.	.	.	.	Ovarian cancer	Ovarian cancer stem cell (hOvCSC)	.	.	15 days	35 mg/kg	.	"In vivo assessment in tumor-bearing animal models classically complements cell cultures data for comparing cancer treatment efficacies. For this reason, hTNBCSC and hOvCSC xenografts were implanted subcutaneously into immunodeficient mice as described in the Methods section with only 1000 cells given their highly tumorigenic nature. Three days later, the animals began receiving weekly IV bolus administration of either vehicle, docetaxel, or TH1902. Docetaxel was administered at a dose (15 mg/kg/week; for 3 cycles) in accordance with the estimated maximal tolerated dose (MTD) for mice, as well as at 1/4 of the MTD (3.75 mg/kg/week). TH1902 was administered at doses (35 and 8.75 mg/kg/week) which contained quantities of docetaxel equivalent to those in the two administrations of free docetaxel. From the size of the hTNBCSC and hOvCSC tumors, it is apparent that docetaxel had little impact on xenografts growth when administered neither at its MTD, for both hTNBCSC and hOvCSC, nor at 1/4 of this dosage as reflected by the growth curves. TH1902, when administered at a dosage equivalent to docetaxel at its MTD, provided greater tumor growth inhibition than did docetaxel for both xenograft models. Furthermore, higher dosage of administered TH1902 (up to 1.5 equivalent of docetaxel MTD) did not generate significant differences in terms of hOvCSC tumor inhibition without affecting mice body weights suggesting that TH1902, even at higher doses, is better tolerated compared to docetaxel. Then, in order to statistically compare the effects of docetaxel and TH1902 on tumor growth, the tumor sizes measured at the vehicle group endpoint were compared and statistically significant differences between the tumor sizes in vehicle-treated animals found in TH1902-treated animals for hTNBCSC and hOvCSC. Mouse body weight was used as an indicator of the morbidity associated with administration of docetaxel or TH1902. Administration of docetaxel at its MTD provoked a weight loss that approached 10% after the treatments, which is often observed in xenograft models with administration of docetaxel at this level. The body weights of animals treated with an equivalent quantity or a 1.5-fold equivalent of TH1902 were maintained at a roughly constant level throughout the experiment. The animals treated with vehicle recorded a slight weight gain (~5%) over this period while animals treated with the lower dosages of docetaxel or TH1902 were similar to the animals treated with vehicle. The body weight data indicates that TH1902 appears to be better tolerated than the equivalent quantity of free docetaxel, in addition to the fact that TH1902 is more efficacious than docetaxel when administered in vivo in the murine models of CSC tested."	"Sortilin (SORT1) is a receptor protein which cycles from the cell surface through intracellular membrane bodies. It binds several circulating proteins and peptides, including progranulin and neurotensin, prior to their rapid intracellular internalization. It is also involved in their intracellular trafficking in endosomal vesicles from the plasma membrane to lysosomes through the endocytic pathway. Deregulation in SORT1 functions has been implicated in cardiovascular disease, Alzheimers disease, and diabetes, whereas its upregulation has been documented in several forms of cancer. Recently, TH1902, a peptide-drug conjugate (PDC) to which two docetaxel molecules were linked to TH19P01 peptide, was generated. TH1902 was demonstrated to recognize and exploit SORT1 functions, and to efficiently inhibit in vitro cell proliferation, and in vivo growth of xenografts from gynecological cancers including triple-negative breast cancer (TNBC)-derived MDA-MB-231 cells, ovarian cancer-derived ES2 and SKOV3 cells, as well as endometrial cancer-derived AN3-CA cells. Interestingly, TH1902 was found to reduce in vitro vasculogenic mimicry (VM) processes in breast and ovarian cancer cells. While some molecular aspects revealing the inter-relationship existence between CSC and VM have been addressed in breast cancer, gastrointestinal cancer, and melanoma, the specific targeting of the CSC subpopulation by TH1902 remains unexplored."
REF00234	PDC_00349	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	79%	%	.	.	.	.	Ovarian cancer	Ovarian cancer stem cell (hOvCSC)	.	.	15 days	42.75 mg/kg	.	"In vivo assessment in tumor-bearing animal models classically complements cell cultures data for comparing cancer treatment efficacies. For this reason, hTNBCSC and hOvCSC xenografts were implanted subcutaneously into immunodeficient mice as described in the Methods section with only 1000 cells given their highly tumorigenic nature. Three days later, the animals began receiving weekly IV bolus administration of either vehicle, docetaxel, or TH1902. Docetaxel was administered at a dose (15 mg/kg/week; for 3 cycles) in accordance with the estimated maximal tolerated dose (MTD) for mice, as well as at 1/4 of the MTD (3.75 mg/kg/week). TH1902 was administered at doses (35 and 8.75 mg/kg/week) which contained quantities of docetaxel equivalent to those in the two administrations of free docetaxel. From the size of the hTNBCSC and hOvCSC tumors, it is apparent that docetaxel had little impact on xenografts growth when administered neither at its MTD, for both hTNBCSC and hOvCSC, nor at 1/4 of this dosage as reflected by the growth curves. TH1902, when administered at a dosage equivalent to docetaxel at its MTD, provided greater tumor growth inhibition than did docetaxel for both xenograft models. Furthermore, higher dosage of administered TH1902 (up to 1.5 equivalent of docetaxel MTD) did not generate significant differences in terms of hOvCSC tumor inhibition without affecting mice body weights suggesting that TH1902, even at higher doses, is better tolerated compared to docetaxel. Then, in order to statistically compare the effects of docetaxel and TH1902 on tumor growth, the tumor sizes measured at the vehicle group endpoint were compared and statistically significant differences between the tumor sizes in vehicle-treated animals found in TH1902-treated animals for hTNBCSC and hOvCSC. Mouse body weight was used as an indicator of the morbidity associated with administration of docetaxel or TH1902. Administration of docetaxel at its MTD provoked a weight loss that approached 10% after the treatments, which is often observed in xenograft models with administration of docetaxel at this level. The body weights of animals treated with an equivalent quantity or a 1.5-fold equivalent of TH1902 were maintained at a roughly constant level throughout the experiment. The animals treated with vehicle recorded a slight weight gain (~5%) over this period while animals treated with the lower dosages of docetaxel or TH1902 were similar to the animals treated with vehicle. The body weight data indicates that TH1902 appears to be better tolerated than the equivalent quantity of free docetaxel, in addition to the fact that TH1902 is more efficacious than docetaxel when administered in vivo in the murine models of CSC tested."	"Sortilin (SORT1) is a receptor protein which cycles from the cell surface through intracellular membrane bodies. It binds several circulating proteins and peptides, including progranulin and neurotensin, prior to their rapid intracellular internalization. It is also involved in their intracellular trafficking in endosomal vesicles from the plasma membrane to lysosomes through the endocytic pathway. Deregulation in SORT1 functions has been implicated in cardiovascular disease, Alzheimers disease, and diabetes, whereas its upregulation has been documented in several forms of cancer. Recently, TH1902, a peptide-drug conjugate (PDC) to which two docetaxel molecules were linked to TH19P01 peptide, was generated. TH1902 was demonstrated to recognize and exploit SORT1 functions, and to efficiently inhibit in vitro cell proliferation, and in vivo growth of xenografts from gynecological cancers including triple-negative breast cancer (TNBC)-derived MDA-MB-231 cells, ovarian cancer-derived ES2 and SKOV3 cells, as well as endometrial cancer-derived AN3-CA cells. Interestingly, TH1902 was found to reduce in vitro vasculogenic mimicry (VM) processes in breast and ovarian cancer cells. While some molecular aspects revealing the inter-relationship existence between CSC and VM have been addressed in breast cancer, gastrointestinal cancer, and melanoma, the specific targeting of the CSC subpopulation by TH1902 remains unexplored."
REF00234	PDC_00349	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor Growth Inhibition value (TGI)	87%	%	.	.	.	.	Ovarian cancer	Ovarian cancer stem cell (hOvCSC)	.	.	15 days	52.5 mg/kg	.	"In vivo assessment in tumor-bearing animal models classically complements cell cultures data for comparing cancer treatment efficacies. For this reason, hTNBCSC and hOvCSC xenografts were implanted subcutaneously into immunodeficient mice as described in the Methods section with only 1000 cells given their highly tumorigenic nature. Three days later, the animals began receiving weekly IV bolus administration of either vehicle, docetaxel, or TH1902. Docetaxel was administered at a dose (15 mg/kg/week; for 3 cycles) in accordance with the estimated maximal tolerated dose (MTD) for mice, as well as at 1/4 of the MTD (3.75 mg/kg/week). TH1902 was administered at doses (35 and 8.75 mg/kg/week) which contained quantities of docetaxel equivalent to those in the two administrations of free docetaxel. From the size of the hTNBCSC and hOvCSC tumors, it is apparent that docetaxel had little impact on xenografts growth when administered neither at its MTD, for both hTNBCSC and hOvCSC, nor at 1/4 of this dosage as reflected by the growth curves. TH1902, when administered at a dosage equivalent to docetaxel at its MTD, provided greater tumor growth inhibition than did docetaxel for both xenograft models. Furthermore, higher dosage of administered TH1902 (up to 1.5 equivalent of docetaxel MTD) did not generate significant differences in terms of hOvCSC tumor inhibition without affecting mice body weights suggesting that TH1902, even at higher doses, is better tolerated compared to docetaxel. Then, in order to statistically compare the effects of docetaxel and TH1902 on tumor growth, the tumor sizes measured at the vehicle group endpoint were compared and statistically significant differences between the tumor sizes in vehicle-treated animals found in TH1902-treated animals for hTNBCSC and hOvCSC. Mouse body weight was used as an indicator of the morbidity associated with administration of docetaxel or TH1902. Administration of docetaxel at its MTD provoked a weight loss that approached 10% after the treatments, which is often observed in xenograft models with administration of docetaxel at this level. The body weights of animals treated with an equivalent quantity or a 1.5-fold equivalent of TH1902 were maintained at a roughly constant level throughout the experiment. The animals treated with vehicle recorded a slight weight gain (~5%) over this period while animals treated with the lower dosages of docetaxel or TH1902 were similar to the animals treated with vehicle. The body weight data indicates that TH1902 appears to be better tolerated than the equivalent quantity of free docetaxel, in addition to the fact that TH1902 is more efficacious than docetaxel when administered in vivo in the murine models of CSC tested."	"Sortilin (SORT1) is a receptor protein which cycles from the cell surface through intracellular membrane bodies. It binds several circulating proteins and peptides, including progranulin and neurotensin, prior to their rapid intracellular internalization. It is also involved in their intracellular trafficking in endosomal vesicles from the plasma membrane to lysosomes through the endocytic pathway. Deregulation in SORT1 functions has been implicated in cardiovascular disease, Alzheimers disease, and diabetes, whereas its upregulation has been documented in several forms of cancer. Recently, TH1902, a peptide-drug conjugate (PDC) to which two docetaxel molecules were linked to TH19P01 peptide, was generated. TH1902 was demonstrated to recognize and exploit SORT1 functions, and to efficiently inhibit in vitro cell proliferation, and in vivo growth of xenografts from gynecological cancers including triple-negative breast cancer (TNBC)-derived MDA-MB-231 cells, ovarian cancer-derived ES2 and SKOV3 cells, as well as endometrial cancer-derived AN3-CA cells. Interestingly, TH1902 was found to reduce in vitro vasculogenic mimicry (VM) processes in breast and ovarian cancer cells. While some molecular aspects revealing the inter-relationship existence between CSC and VM have been addressed in breast cancer, gastrointestinal cancer, and melanoma, the specific targeting of the CSC subpopulation by TH1902 remains unexplored."
REF00232	PDC_00069	Breast cancer	BALB/c nude mice triple-negative breast cancer cell-derived xenograft model.	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	60%	%	.	.	.	.	.	.	1-2 h	.	28 days	1 mg/kg	.	"BT8009 demonstrated dose-related effects on tumor growth in CDX and PDX models over the range 1-3 mg/kg when administered qw. Full tumor regressions were routinely achieved in both models with 3 mg/kg, with no tumor regrowth in subsequent weeks off treatment. Stable disease was delivered by 2 mg/kg and at this dose, in the PDX model, tumor growth resumed after drug cessation. In both models animals from the vehicle treated group were treated with 3 mg/kg BT8009 when tumors reached approximately 800 mm3or 1,000 mm3. Profound tumor regression was rapidly initiated in response. In the majority of studies 3 mg/kg, qw, was adopted as the standard dosing regimen."	"The cell adhesion molecule Nectin-4 shows elevated expression in multiple tumor types correlated with poor prognosis. Nectin-4-directed ADCs show efficacy in multiple xenograft tumor models. The ADC enfortumab vedotin (EV) delivers the antimitotic toxin MMAE to Nectin-4-expressing cells via internalization and cleavage of a valine-citrulline dipeptide linker component. Clinical validation of Nectin-4 as a target in urothelial cancer has been demonstrated with EV. In 2021, the FDA-approved EV for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin containing chemotherapy and had received one or more prior lines of therapy. Bicycle toxin conjugates (BTC) are structurally constrained bicyclic peptides conjugated through cleavable linkers to a toxin. Various, well-described linker toxin combinations can be incorporated into the BTC molecule (e.g., BT1718 and BT5528; refs.). They are of low molecular weight (approximately 4-4.5 kDa) and being chemically synthesized can be optimized for appropriate affinity, stability, and solubility relatively simply. Through intravenous administration, high systemic Cmax values can be attained, which, along with BTCs relatively small size, helps drive rapid diffusion into extra-vascular compartment, as reflected in a volume of distribution similar to extracellular fluid. We believe that delivery of a high number of BTCs, each carrying a reduced toxin load (peptide toxin ratio of 1:1) should improve tumor penetration and reduce the impact of the binding site barrier. BTCs show moderate clearance from the systemic vasculature, predominantly by the renal route. This overall profile marks them out from most ADCs and provides the possibility of enhanced clinical efficacy with a wider therapeutic index. BTCs are new therapeutic modality that shows a very different pharmacokinetic and structural profile to classic ADCs, whereas possessing robust tumoricidal properties. BTCs targeting MT1-MMP and EphA2 are currently in clinical trials. BT8009 is the most recent BTC to enter clinical trial. BT8009 is highly selective for Nectin-4 over other nectin family members and an extensive range of cell membrane expressed proteins. It shares the same cleavable linker and toxin combination as EV and can be cleaved by proteases in the TME, releasing cell penetrant MMAE that diffuses into tumor cells, or bystander stromal-supportive cells, evoking cell death, and tumor regression. It shows a robust and dose-dependent antitumor activity in multiple CDX and PDX models, representing lung, breast, bladder, head and neck cancers. Optimal tumor regression is associated with membrane expression of Nectin-4, in conjunction with MMAE sensitivity. Tumor regression rates are comparable for small and large tumors, indicative of deep and rapid penetration throughout the tumor. BT8009 provides tumoricidal activity with several regimens, potentially allowing for clinical titration of dose and dose interval if required."
REF00232	PDC_00069	Breast cancer	BALB/c nude mice triple-negative breast cancer cell-derived xenograft model.	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	74%	%	.	.	.	.	.	.	1-2 h	.	28 days	2 mg/kg	.	"BT8009 demonstrated dose-related effects on tumor growth in CDX and PDX models over the range 1-3 mg/kg when administered qw. Full tumor regressions were routinely achieved in both models with 3 mg/kg, with no tumor regrowth in subsequent weeks off treatment. Stable disease was delivered by 2 mg/kg and at this dose, in the PDX model, tumor growth resumed after drug cessation. In both models animals from the vehicle treated group were treated with 3 mg/kg BT8009 when tumors reached approximately 800 mm3or 1,000 mm3. Profound tumor regression was rapidly initiated in response. In the majority of studies 3 mg/kg, qw, was adopted as the standard dosing regimen."	"The cell adhesion molecule Nectin-4 shows elevated expression in multiple tumor types correlated with poor prognosis. Nectin-4-directed ADCs show efficacy in multiple xenograft tumor models. The ADC enfortumab vedotin (EV) delivers the antimitotic toxin MMAE to Nectin-4-expressing cells via internalization and cleavage of a valine-citrulline dipeptide linker component. Clinical validation of Nectin-4 as a target in urothelial cancer has been demonstrated with EV. In 2021, the FDA-approved EV for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin containing chemotherapy and had received one or more prior lines of therapy. Bicycle toxin conjugates (BTC) are structurally constrained bicyclic peptides conjugated through cleavable linkers to a toxin. Various, well-described linker toxin combinations can be incorporated into the BTC molecule (e.g., BT1718 and BT5528; refs.). They are of low molecular weight (approximately 4-4.5 kDa) and being chemically synthesized can be optimized for appropriate affinity, stability, and solubility relatively simply. Through intravenous administration, high systemic Cmax values can be attained, which, along with BTCs relatively small size, helps drive rapid diffusion into extra-vascular compartment, as reflected in a volume of distribution similar to extracellular fluid. We believe that delivery of a high number of BTCs, each carrying a reduced toxin load (peptide toxin ratio of 1:1) should improve tumor penetration and reduce the impact of the binding site barrier. BTCs show moderate clearance from the systemic vasculature, predominantly by the renal route. This overall profile marks them out from most ADCs and provides the possibility of enhanced clinical efficacy with a wider therapeutic index. BTCs are new therapeutic modality that shows a very different pharmacokinetic and structural profile to classic ADCs, whereas possessing robust tumoricidal properties. BTCs targeting MT1-MMP and EphA2 are currently in clinical trials. BT8009 is the most recent BTC to enter clinical trial. BT8009 is highly selective for Nectin-4 over other nectin family members and an extensive range of cell membrane expressed proteins. It shares the same cleavable linker and toxin combination as EV and can be cleaved by proteases in the TME, releasing cell penetrant MMAE that diffuses into tumor cells, or bystander stromal-supportive cells, evoking cell death, and tumor regression. It shows a robust and dose-dependent antitumor activity in multiple CDX and PDX models, representing lung, breast, bladder, head and neck cancers. Optimal tumor regression is associated with membrane expression of Nectin-4, in conjunction with MMAE sensitivity. Tumor regression rates are comparable for small and large tumors, indicative of deep and rapid penetration throughout the tumor. BT8009 provides tumoricidal activity with several regimens, potentially allowing for clinical titration of dose and dose interval if required."
REF00232	PDC_00069	Breast cancer	BALB/c nude mice triple-negative breast cancer cell-derived xenograft model.	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	96%	%	.	.	.	.	.	.	1-2 h	.	28 days	3 mg/kg	.	"BT8009 demonstrated dose-related effects on tumor growth in CDX and PDX models over the range 1-3 mg/kg when administered qw. Full tumor regressions were routinely achieved in both models with 3 mg/kg, with no tumor regrowth in subsequent weeks off treatment. Stable disease was delivered by 2 mg/kg and at this dose, in the PDX model, tumor growth resumed after drug cessation. In both models animals from the vehicle treated group were treated with 3 mg/kg BT8009 when tumors reached approximately 800 mm3or 1,000 mm3. Profound tumor regression was rapidly initiated in response. In the majority of studies 3 mg/kg, qw, was adopted as the standard dosing regimen."	"The cell adhesion molecule Nectin-4 shows elevated expression in multiple tumor types correlated with poor prognosis. Nectin-4-directed ADCs show efficacy in multiple xenograft tumor models. The ADC enfortumab vedotin (EV) delivers the antimitotic toxin MMAE to Nectin-4-expressing cells via internalization and cleavage of a valine-citrulline dipeptide linker component. Clinical validation of Nectin-4 as a target in urothelial cancer has been demonstrated with EV. In 2021, the FDA-approved EV for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin containing chemotherapy and had received one or more prior lines of therapy. Bicycle toxin conjugates (BTC) are structurally constrained bicyclic peptides conjugated through cleavable linkers to a toxin. Various, well-described linker toxin combinations can be incorporated into the BTC molecule (e.g., BT1718 and BT5528; refs.). They are of low molecular weight (approximately 4-4.5 kDa) and being chemically synthesized can be optimized for appropriate affinity, stability, and solubility relatively simply. Through intravenous administration, high systemic Cmax values can be attained, which, along with BTCs relatively small size, helps drive rapid diffusion into extra-vascular compartment, as reflected in a volume of distribution similar to extracellular fluid. We believe that delivery of a high number of BTCs, each carrying a reduced toxin load (peptide toxin ratio of 1:1) should improve tumor penetration and reduce the impact of the binding site barrier. BTCs show moderate clearance from the systemic vasculature, predominantly by the renal route. This overall profile marks them out from most ADCs and provides the possibility of enhanced clinical efficacy with a wider therapeutic index. BTCs are new therapeutic modality that shows a very different pharmacokinetic and structural profile to classic ADCs, whereas possessing robust tumoricidal properties. BTCs targeting MT1-MMP and EphA2 are currently in clinical trials. BT8009 is the most recent BTC to enter clinical trial. BT8009 is highly selective for Nectin-4 over other nectin family members and an extensive range of cell membrane expressed proteins. It shares the same cleavable linker and toxin combination as EV and can be cleaved by proteases in the TME, releasing cell penetrant MMAE that diffuses into tumor cells, or bystander stromal-supportive cells, evoking cell death, and tumor regression. It shows a robust and dose-dependent antitumor activity in multiple CDX and PDX models, representing lung, breast, bladder, head and neck cancers. Optimal tumor regression is associated with membrane expression of Nectin-4, in conjunction with MMAE sensitivity. Tumor regression rates are comparable for small and large tumors, indicative of deep and rapid penetration throughout the tumor. BT8009 provides tumoricidal activity with several regimens, potentially allowing for clinical titration of dose and dose interval if required."
REF00232	PDC_00069	Breast cancer	BALB/c nude mice non-small cell lung cell-derived xenograft model.	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	23%	%	.	.	.	.	.	.	1-2 h	.	28 days	1 mg/kg	.	"BT8009 demonstrated dose-related effects on tumor growth in CDX and PDX models over the range 1-3 mg/kg when administered qw. Full tumor regressions were routinely achieved in both models with 3 mg/kg, with no tumor regrowth in subsequent weeks off treatment. Stable disease was delivered by 2 mg/kg and at this dose, in the PDX model, tumor growth resumed after drug cessation. In both models animals from the vehicle treated group were treated with 3 mg/kg BT8009 when tumors reached approximately 800 mm3or 1,000 mm3. Profound tumor regression was rapidly initiated in response. In the majority of studies 3 mg/kg, qw, was adopted as the standard dosing regimen."	"The cell adhesion molecule Nectin-4 shows elevated expression in multiple tumor types correlated with poor prognosis. Nectin-4-directed ADCs show efficacy in multiple xenograft tumor models. The ADC enfortumab vedotin (EV) delivers the antimitotic toxin MMAE to Nectin-4-expressing cells via internalization and cleavage of a valine-citrulline dipeptide linker component. Clinical validation of Nectin-4 as a target in urothelial cancer has been demonstrated with EV. In 2021, the FDA-approved EV for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin containing chemotherapy and had received one or more prior lines of therapy. Bicycle toxin conjugates (BTC) are structurally constrained bicyclic peptides conjugated through cleavable linkers to a toxin. Various, well-described linker toxin combinations can be incorporated into the BTC molecule (e.g., BT1718 and BT5528; refs.). They are of low molecular weight (approximately 4-4.5 kDa) and being chemically synthesized can be optimized for appropriate affinity, stability, and solubility relatively simply. Through intravenous administration, high systemic Cmax values can be attained, which, along with BTCs relatively small size, helps drive rapid diffusion into extra-vascular compartment, as reflected in a volume of distribution similar to extracellular fluid. We believe that delivery of a high number of BTCs, each carrying a reduced toxin load (peptide toxin ratio of 1:1) should improve tumor penetration and reduce the impact of the binding site barrier. BTCs show moderate clearance from the systemic vasculature, predominantly by the renal route. This overall profile marks them out from most ADCs and provides the possibility of enhanced clinical efficacy with a wider therapeutic index. BTCs are new therapeutic modality that shows a very different pharmacokinetic and structural profile to classic ADCs, whereas possessing robust tumoricidal properties. BTCs targeting MT1-MMP and EphA2 are currently in clinical trials. BT8009 is the most recent BTC to enter clinical trial. BT8009 is highly selective for Nectin-4 over other nectin family members and an extensive range of cell membrane expressed proteins. It shares the same cleavable linker and toxin combination as EV and can be cleaved by proteases in the TME, releasing cell penetrant MMAE that diffuses into tumor cells, or bystander stromal-supportive cells, evoking cell death, and tumor regression. It shows a robust and dose-dependent antitumor activity in multiple CDX and PDX models, representing lung, breast, bladder, head and neck cancers. Optimal tumor regression is associated with membrane expression of Nectin-4, in conjunction with MMAE sensitivity. Tumor regression rates are comparable for small and large tumors, indicative of deep and rapid penetration throughout the tumor. BT8009 provides tumoricidal activity with several regimens, potentially allowing for clinical titration of dose and dose interval if required."
REF00232	PDC_00069	Breast cancer	BALB/c nude mice non-small cell lung cell-derived xenograft model.	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	77%	%	.	.	.	.	.	.	1-2 h	.	28 days	2 mg/kg	.	"BT8009 demonstrated dose-related effects on tumor growth in CDX and PDX models over the range 1-3 mg/kg when administered qw. Full tumor regressions were routinely achieved in both models with 3 mg/kg, with no tumor regrowth in subsequent weeks off treatment. Stable disease was delivered by 2 mg/kg and at this dose, in the PDX model, tumor growth resumed after drug cessation. In both models animals from the vehicle treated group were treated with 3 mg/kg BT8009 when tumors reached approximately 800 mm3or 1,000 mm3. Profound tumor regression was rapidly initiated in response. In the majority of studies 3 mg/kg, qw, was adopted as the standard dosing regimen."	"The cell adhesion molecule Nectin-4 shows elevated expression in multiple tumor types correlated with poor prognosis. Nectin-4-directed ADCs show efficacy in multiple xenograft tumor models. The ADC enfortumab vedotin (EV) delivers the antimitotic toxin MMAE to Nectin-4-expressing cells via internalization and cleavage of a valine-citrulline dipeptide linker component. Clinical validation of Nectin-4 as a target in urothelial cancer has been demonstrated with EV. In 2021, the FDA-approved EV for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin containing chemotherapy and had received one or more prior lines of therapy. Bicycle toxin conjugates (BTC) are structurally constrained bicyclic peptides conjugated through cleavable linkers to a toxin. Various, well-described linker toxin combinations can be incorporated into the BTC molecule (e.g., BT1718 and BT5528; refs.). They are of low molecular weight (approximately 4-4.5 kDa) and being chemically synthesized can be optimized for appropriate affinity, stability, and solubility relatively simply. Through intravenous administration, high systemic Cmax values can be attained, which, along with BTCs relatively small size, helps drive rapid diffusion into extra-vascular compartment, as reflected in a volume of distribution similar to extracellular fluid. We believe that delivery of a high number of BTCs, each carrying a reduced toxin load (peptide toxin ratio of 1:1) should improve tumor penetration and reduce the impact of the binding site barrier. BTCs show moderate clearance from the systemic vasculature, predominantly by the renal route. This overall profile marks them out from most ADCs and provides the possibility of enhanced clinical efficacy with a wider therapeutic index. BTCs are new therapeutic modality that shows a very different pharmacokinetic and structural profile to classic ADCs, whereas possessing robust tumoricidal properties. BTCs targeting MT1-MMP and EphA2 are currently in clinical trials. BT8009 is the most recent BTC to enter clinical trial. BT8009 is highly selective for Nectin-4 over other nectin family members and an extensive range of cell membrane expressed proteins. It shares the same cleavable linker and toxin combination as EV and can be cleaved by proteases in the TME, releasing cell penetrant MMAE that diffuses into tumor cells, or bystander stromal-supportive cells, evoking cell death, and tumor regression. It shows a robust and dose-dependent antitumor activity in multiple CDX and PDX models, representing lung, breast, bladder, head and neck cancers. Optimal tumor regression is associated with membrane expression of Nectin-4, in conjunction with MMAE sensitivity. Tumor regression rates are comparable for small and large tumors, indicative of deep and rapid penetration throughout the tumor. BT8009 provides tumoricidal activity with several regimens, potentially allowing for clinical titration of dose and dose interval if required."
REF00232	PDC_00069	Breast cancer	BALB/c nude mice non-small cell lung cell-derived xenograft model.	Identified from the Human Clinical Data	High Expreesion	Tumor Growth Inhibition value (TGI)	98%	%	.	.	.	.	.	.	1-2 h	.	28 days	3 mg/kg	.	"BT8009 demonstrated dose-related effects on tumor growth in CDX and PDX models over the range 1-3 mg/kg when administered qw. Full tumor regressions were routinely achieved in both models with 3 mg/kg, with no tumor regrowth in subsequent weeks off treatment. Stable disease was delivered by 2 mg/kg and at this dose, in the PDX model, tumor growth resumed after drug cessation. In both models animals from the vehicle treated group were treated with 3 mg/kg BT8009 when tumors reached approximately 800 mm3or 1,000 mm3. Profound tumor regression was rapidly initiated in response. In the majority of studies 3 mg/kg, qw, was adopted as the standard dosing regimen."	"The cell adhesion molecule Nectin-4 shows elevated expression in multiple tumor types correlated with poor prognosis. Nectin-4-directed ADCs show efficacy in multiple xenograft tumor models. The ADC enfortumab vedotin (EV) delivers the antimitotic toxin MMAE to Nectin-4-expressing cells via internalization and cleavage of a valine-citrulline dipeptide linker component. Clinical validation of Nectin-4 as a target in urothelial cancer has been demonstrated with EV. In 2021, the FDA-approved EV for patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or were ineligible for cisplatin containing chemotherapy and had received one or more prior lines of therapy. Bicycle toxin conjugates (BTC) are structurally constrained bicyclic peptides conjugated through cleavable linkers to a toxin. Various, well-described linker toxin combinations can be incorporated into the BTC molecule (e.g., BT1718 and BT5528; refs.). They are of low molecular weight (approximately 4-4.5 kDa) and being chemically synthesized can be optimized for appropriate affinity, stability, and solubility relatively simply. Through intravenous administration, high systemic Cmax values can be attained, which, along with BTCs relatively small size, helps drive rapid diffusion into extra-vascular compartment, as reflected in a volume of distribution similar to extracellular fluid. We believe that delivery of a high number of BTCs, each carrying a reduced toxin load (peptide toxin ratio of 1:1) should improve tumor penetration and reduce the impact of the binding site barrier. BTCs show moderate clearance from the systemic vasculature, predominantly by the renal route. This overall profile marks them out from most ADCs and provides the possibility of enhanced clinical efficacy with a wider therapeutic index. BTCs are new therapeutic modality that shows a very different pharmacokinetic and structural profile to classic ADCs, whereas possessing robust tumoricidal properties. BTCs targeting MT1-MMP and EphA2 are currently in clinical trials. BT8009 is the most recent BTC to enter clinical trial. BT8009 is highly selective for Nectin-4 over other nectin family members and an extensive range of cell membrane expressed proteins. It shares the same cleavable linker and toxin combination as EV and can be cleaved by proteases in the TME, releasing cell penetrant MMAE that diffuses into tumor cells, or bystander stromal-supportive cells, evoking cell death, and tumor regression. It shows a robust and dose-dependent antitumor activity in multiple CDX and PDX models, representing lung, breast, bladder, head and neck cancers. Optimal tumor regression is associated with membrane expression of Nectin-4, in conjunction with MMAE sensitivity. Tumor regression rates are comparable for small and large tumors, indicative of deep and rapid penetration throughout the tumor. BT8009 provides tumoricidal activity with several regimens, potentially allowing for clinical titration of dose and dose interval if required."
REF00230	PDC_00244	Metastatic triple-negative breast cancer	BRCA1 mut MDA-MB-436 cells female BALB/cnude mice xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	64.60%	%	.	.	.	.	Invasive breast carcinoma of no special type	BRCA1 mut MDA-MB-436 cell	.	.	3 weeks	3 mg/kg	.	"To examine whether BRCA and PTEN alteration status affect the anti-tumor efficacy of olaparib/MPD3 combination, we performedin vivoexperiments on Hs578t-tumor and BT549-tumor bearing balb/cnude mice. As expected, olaparib monotherapy in Hs578t or BT549 tumors did not show detectable tumor suppressing efficacy, which could be ascribed to the poor sensitivity of olaparib in BRCA wild-type tumors. Interestingly, Hs578t tumors showed delayed onset of tumor growth inhibition effect by MPD3 monotherapy, producing 48.4% TGI rate on the last day of observation. Following an unexpected response to MPD3 in PTEN wild-type tumors, different control tumor specimens at day 1, 16, and 28 were examined by immunohistochemical staining to investigate tumor microenvironmental changes during the drug treatment course. We found evidence of increasing pattern of active caspase-3 expression over the course of time, which is thought to be associated with activation of localized extracellular prodrug and late tumor inhibiting efficacy in Hs578t tumors. Owing to the poor response to olaparib therapy, both MPD3 and olaparib/MPD3 displayed similar tumor inhibiting efficacies in Hs578t tumor bearing mice, suggesting that olaparib triggered apoptosis is needed to generate synergistic efficacy with MPD3. Lastly,in vivoexperiment results with BT549 tumor xenografted model confirmed the contribution of PTEN-loss alteration to thein vivoactivity of MPD3. MPD3 monotherapy was able to induce substantial tumor growth inhibition with 63.4% TGI. We ascribe these results mainly to the PTEN-loss induced upregulation of the macropinocytosis level, witnessed by significantly increased albumin uptake level in BT549cells. However, as with Hs578t xenograft model, the addition of olaparib did not cause significant tumor growth inhibition. Note that despite the comparable anti-cancer activity of olaparib/docetaxel to that of olaparib/MPD3, docetaxel combination treatment caused severebody weight loss, with 60% and 20% lethality in Hs578t and in BT549 tumor bearing mice, respectively. The results ofin vivoanti-cancer efficacies of MPD3 and olaparib in TNBC tumor models expressing different biomarkers are summarized inTable 1. Coefficients of drug interaction (CDI) values of the combination of olaparib/MPD3 were 0.04, 1.22 and 0.42 in MDA-MB-436, Hs578t, BT549 xenograft models, respectively, where CDI of <1, =1, or >1 indicates that the combination therapy is synergistic, additive, or antagonistic. These results provide compelling evidence that the BRCA and PTEN alteration status influence the efficacy of our combination strategy, showing that BRCA mutation and PTEN-loss contribute to the favorable anti-cancer efficacy of the strategy."	"To demonstrate our strategy, we developed a peptide-drug conjugate (PDC) composed of the caspase-3 cleavablepeptide sequence(DEVD), an albumin-binding functional moiety, and docetaxel linked to the peptide via self-immolated linker. Functionalization of albumin-binding domain enables intravenously injected PDC to spontaneously bind to circulatingserum albumin, which is employed as a drug carrier capable of inducing macropinocytic uptake of the conjugate. Furthermore, in order to combat tumoral heterogeneity, a unique peptide sequence of DEVD is deployed, which is a core component of the PDC that propagates bystander killing of cancer cells. More specifically, caspase-3 is triggered from albumin-metabolism induced apoptosis in PTEN-loss cancer cells, which in turn recognizes and activates extracellular PDC to release the payload. The released hydrophobic payload subsequently penetrates neighboring cancer cells, thereby inducing bystander killing in a non-selective manner, leading to the continual amplification ofin-situapoptosis. Additionally, to boost the apoptosis of initial cancer cells and caspase-3 expression, we used olaparib as a combination therapeutic agent. Given that olaparib is the first targeted therapy approved against metastatic TNBC with BRCA mutation, we reasoned that combination therapy with olaparib has the potential to induce apoptosis in BRCA mutant cancer cells and intensify tumoral apoptosis. In this study, we demonstrate the therapeutic potential of exploiting PTEN-loss drivenbiomimeticdrug delivery and the significant therapeutic benefit of combination therapy in the treatment of metastatic TNBC with altered PTEN and BRCA using our novel PDC."
REF00230	PDC_00244	Metastatic triple-negative breast cancer	BRCA/PTEN wt Hs578t cells female BALB/cnude mice xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	48.40%	%	.	.	.	.	Invasive breast carcinoma of no special type	BRCA/PTEN WT Hs578t cell	.	.	3 weeks	3 mg/kg	.	"To examine whether BRCA and PTEN alteration status affect the anti-tumor efficacy of olaparib/MPD3 combination, we performedin vivoexperiments on Hs578t-tumor and BT549-tumor bearing balb/cnude mice. As expected, olaparib monotherapy in Hs578t or BT549 tumors did not show detectable tumor suppressing efficacy, which could be ascribed to the poor sensitivity of olaparib in BRCA wild-type tumors. Interestingly, Hs578t tumors showed delayed onset of tumor growth inhibition effect by MPD3 monotherapy, producing 48.4% TGI rate on the last day of observation. Following an unexpected response to MPD3 in PTEN wild-type tumors, different control tumor specimens at day 1, 16, and 28 were examined by immunohistochemical staining to investigate tumor microenvironmental changes during the drug treatment course. We found evidence of increasing pattern of active caspase-3 expression over the course of time, which is thought to be associated with activation of localized extracellular prodrug and late tumor inhibiting efficacy in Hs578t tumors. Owing to the poor response to olaparib therapy, both MPD3 and olaparib/MPD3 displayed similar tumor inhibiting efficacies in Hs578t tumor bearing mice, suggesting that olaparib triggered apoptosis is needed to generate synergistic efficacy with MPD3. Lastly,in vivoexperiment results with BT549 tumor xenografted model confirmed the contribution of PTEN-loss alteration to thein vivoactivity of MPD3. MPD3 monotherapy was able to induce substantial tumor growth inhibition with 63.4% TGI. We ascribe these results mainly to the PTEN-loss induced upregulation of the macropinocytosis level, witnessed by significantly increased albumin uptake level in BT549cells. However, as with Hs578t xenograft model, the addition of olaparib did not cause significant tumor growth inhibition. Note that despite the comparable anti-cancer activity of olaparib/docetaxel to that of olaparib/MPD3, docetaxel combination treatment caused severebody weight loss, with 60% and 20% lethality in Hs578t and in BT549 tumor bearing mice, respectively. The results ofin vivoanti-cancer efficacies of MPD3 and olaparib in TNBC tumor models expressing different biomarkers are summarized inTable 1. Coefficients of drug interaction (CDI) values of the combination of olaparib/MPD3 were 0.04, 1.22 and 0.42 in MDA-MB-436, Hs578t, BT549 xenograft models, respectively, where CDI of <1, =1, or >1 indicates that the combination therapy is synergistic, additive, or antagonistic. These results provide compelling evidence that the BRCA and PTEN alteration status influence the efficacy of our combination strategy, showing that BRCA mutation and PTEN-loss contribute to the favorable anti-cancer efficacy of the strategy."	"To demonstrate our strategy, we developed a peptide-drug conjugate (PDC) composed of the caspase-3 cleavablepeptide sequence(DEVD), an albumin-binding functional moiety, and docetaxel linked to the peptide via self-immolated linker. Functionalization of albumin-binding domain enables intravenously injected PDC to spontaneously bind to circulatingserum albumin, which is employed as a drug carrier capable of inducing macropinocytic uptake of the conjugate. Furthermore, in order to combat tumoral heterogeneity, a unique peptide sequence of DEVD is deployed, which is a core component of the PDC that propagates bystander killing of cancer cells. More specifically, caspase-3 is triggered from albumin-metabolism induced apoptosis in PTEN-loss cancer cells, which in turn recognizes and activates extracellular PDC to release the payload. The released hydrophobic payload subsequently penetrates neighboring cancer cells, thereby inducing bystander killing in a non-selective manner, leading to the continual amplification ofin-situapoptosis. Additionally, to boost the apoptosis of initial cancer cells and caspase-3 expression, we used olaparib as a combination therapeutic agent. Given that olaparib is the first targeted therapy approved against metastatic TNBC with BRCA mutation, we reasoned that combination therapy with olaparib has the potential to induce apoptosis in BRCA mutant cancer cells and intensify tumoral apoptosis. In this study, we demonstrate the therapeutic potential of exploiting PTEN-loss drivenbiomimeticdrug delivery and the significant therapeutic benefit of combination therapy in the treatment of metastatic TNBC with altered PTEN and BRCA using our novel PDC."
REF00230	PDC_00244	Metastatic triple-negative breast cancer	BRCA wt BT549 cells female BALB/cnude mice xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	63.40%	%	.	.	.	.	Invasive breast carcinoma of no special type	BRCA WT BT-549 cell	.	.	3 weeks	3 mg/kg	.	"To examine whether BRCA and PTEN alteration status affect the anti-tumor efficacy of olaparib/MPD3 combination, we performedin vivoexperiments on Hs578t-tumor and BT549-tumor bearing balb/cnude mice. As expected, olaparib monotherapy in Hs578t or BT549 tumors did not show detectable tumor suppressing efficacy, which could be ascribed to the poor sensitivity of olaparib in BRCA wild-type tumors. Interestingly, Hs578t tumors showed delayed onset of tumor growth inhibition effect by MPD3 monotherapy, producing 48.4% TGI rate on the last day of observation. Following an unexpected response to MPD3 in PTEN wild-type tumors, different control tumor specimens at day 1, 16, and 28 were examined by immunohistochemical staining to investigate tumor microenvironmental changes during the drug treatment course. We found evidence of increasing pattern of active caspase-3 expression over the course of time, which is thought to be associated with activation of localized extracellular prodrug and late tumor inhibiting efficacy in Hs578t tumors. Owing to the poor response to olaparib therapy, both MPD3 and olaparib/MPD3 displayed similar tumor inhibiting efficacies in Hs578t tumor bearing mice, suggesting that olaparib triggered apoptosis is needed to generate synergistic efficacy with MPD3. Lastly,in vivoexperiment results with BT549 tumor xenografted model confirmed the contribution of PTEN-loss alteration to thein vivoactivity of MPD3. MPD3 monotherapy was able to induce substantial tumor growth inhibition with 63.4% TGI. We ascribe these results mainly to the PTEN-loss induced upregulation of the macropinocytosis level, witnessed by significantly increased albumin uptake level in BT549cells. However, as with Hs578t xenograft model, the addition of olaparib did not cause significant tumor growth inhibition. Note that despite the comparable anti-cancer activity of olaparib/docetaxel to that of olaparib/MPD3, docetaxel combination treatment caused severebody weight loss, with 60% and 20% lethality in Hs578t and in BT549 tumor bearing mice, respectively. The results ofin vivoanti-cancer efficacies of MPD3 and olaparib in TNBC tumor models expressing different biomarkers are summarized inTable 1. Coefficients of drug interaction (CDI) values of the combination of olaparib/MPD3 were 0.04, 1.22 and 0.42 in MDA-MB-436, Hs578t, BT549 xenograft models, respectively, where CDI of <1, =1, or >1 indicates that the combination therapy is synergistic, additive, or antagonistic. These results provide compelling evidence that the BRCA and PTEN alteration status influence the efficacy of our combination strategy, showing that BRCA mutation and PTEN-loss contribute to the favorable anti-cancer efficacy of the strategy."	"To demonstrate our strategy, we developed a peptide-drug conjugate (PDC) composed of the caspase-3 cleavablepeptide sequence(DEVD), an albumin-binding functional moiety, and docetaxel linked to the peptide via self-immolated linker. Functionalization of albumin-binding domain enables intravenously injected PDC to spontaneously bind to circulatingserum albumin, which is employed as a drug carrier capable of inducing macropinocytic uptake of the conjugate. Furthermore, in order to combat tumoral heterogeneity, a unique peptide sequence of DEVD is deployed, which is a core component of the PDC that propagates bystander killing of cancer cells. More specifically, caspase-3 is triggered from albumin-metabolism induced apoptosis in PTEN-loss cancer cells, which in turn recognizes and activates extracellular PDC to release the payload. The released hydrophobic payload subsequently penetrates neighboring cancer cells, thereby inducing bystander killing in a non-selective manner, leading to the continual amplification ofin-situapoptosis. Additionally, to boost the apoptosis of initial cancer cells and caspase-3 expression, we used olaparib as a combination therapeutic agent. Given that olaparib is the first targeted therapy approved against metastatic TNBC with BRCA mutation, we reasoned that combination therapy with olaparib has the potential to induce apoptosis in BRCA mutant cancer cells and intensify tumoral apoptosis. In this study, we demonstrate the therapeutic potential of exploiting PTEN-loss drivenbiomimeticdrug delivery and the significant therapeutic benefit of combination therapy in the treatment of metastatic TNBC with altered PTEN and BRCA using our novel PDC."
REF00226	PDC_00051	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.87 nM	nM	.	.	.	.	Gastric signet ring cell adenocarcinoma	NUGC-4 cell	.	.	72 h	.	.	"We next evaluated the in vitro cytotoxicity of 1131-MMAE. NUGC-4, MKN45 and HGC27 cells were drug-treated for 72 h and their viability was assessed. 1131-MMAE killed KK-LC-1 positive gastric cancer cells with high potency. The IC50 values of 1131-MMAE were 3.87 nM for NUGC-4 cells and 5.26 nM for MKN45 cells. However, although a very high concentration was used, 1131-MMAE could only moderately inhibit the viability of KK-LC-1 negative HGC27 cells. The IC50 value of 1131-MMAE for HGC27 cells was 100-200 times higher than that in NUGC-4 and MNK45 cells. Free MMAE exerted cytotoxicity irrespective of the KK-LC-1 expression status. The IC50 values of free MMAE were 10.97 nM for NUGC-4 cells, 10.70 nM for MKN45 cells and 7.18 nM for HGC27 cells. Naked 1131 peptide showed no cytotoxicity to all three cell lines. These results were consistent with the KK-LC-1-dependent endocytosis and confirmed the target-selective killing of 1131-MMAE."	.
REF00226	PDC_00051	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.26 nM	nM	.	.	.	.	Gastric adenocarcinoma	MKN45 cell	.	.	72 h	.	.	"We next evaluated the in vitro cytotoxicity of 1131-MMAE. NUGC-4, MKN45 and HGC27 cells were drug-treated for 72 h and their viability was assessed. 1131-MMAE killed KK-LC-1 positive gastric cancer cells with high potency. The IC50 values of 1131-MMAE were 3.87 nM for NUGC-4 cells and 5.26 nM for MKN45 cells. However, although a very high concentration was used, 1131-MMAE could only moderately inhibit the viability of KK-LC-1 negative HGC27 cells. The IC50 value of 1131-MMAE for HGC27 cells was 100-200 times higher than that in NUGC-4 and MNK45 cells. Free MMAE exerted cytotoxicity irrespective of the KK-LC-1 expression status. The IC50 values of free MMAE were 10.97 nM for NUGC-4 cells, 10.70 nM for MKN45 cells and 7.18 nM for HGC27 cells. Naked 1131 peptide showed no cytotoxicity to all three cell lines. These results were consistent with the KK-LC-1-dependent endocytosis and confirmed the target-selective killing of 1131-MMAE."	.
REF00226	PDC_00051	Gastric cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	786 nM	nM	.	.	.	.	Gastric carcinoma	HGC-27 cell	.	.	72 h	.	.	"We next evaluated the in vitro cytotoxicity of 1131-MMAE. NUGC-4, MKN45 and HGC27 cells were drug-treated for 72 h and their viability was assessed. 1131-MMAE killed KK-LC-1 positive gastric cancer cells with high potency. The IC50 values of 1131-MMAE were 3.87 nM for NUGC-4 cells and 5.26 nM for MKN45 cells. However, although a very high concentration was used, 1131-MMAE could only moderately inhibit the viability of KK-LC-1 negative HGC27 cells. The IC50 value of 1131-MMAE for HGC27 cells was 100-200 times higher than that in NUGC-4 and MNK45 cells. Free MMAE exerted cytotoxicity irrespective of the KK-LC-1 expression status. The IC50 values of free MMAE were 10.97 nM for NUGC-4 cells, 10.70 nM for MKN45 cells and 7.18 nM for HGC27 cells. Naked 1131 peptide showed no cytotoxicity to all three cell lines. These results were consistent with the KK-LC-1-dependent endocytosis and confirmed the target-selective killing of 1131-MMAE."	.
REF00225	PDC_00342	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	2.26 &plusmn; 0.31 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	72 h	.	MTT assay	"To deliver the functional molecule into the cells, we attached an anticancer drug, methotrexate (MTX), to the N-terminus of STRAPs. The peptides were tested for their capability to deliver the active drug molecule in breast and cervical cancer cells. MDA-MB-231 and HeLa cells were treated with varying concentrations of MTX and STRAP-MTX conjugates for 72 h. Cell viability was assessed using the MTT assay. The cytotoxicity of MTX increased when delivered as peptide-MTX conjugates to the cells. This resulted in an overall reduction in the inhibitory concentration cytotoxic to 50% of cells (IC50) for MTX. The MTX resistance for MDA-MB-231 cells is well-established. The IC50 for MTX in MDA-MB-231 cells was minimum when delivered as a STRAP-4-MTX conjugate. Similar lowering of IC50 values in HeLa cells was observed. We also treated HEK-293 cells with MTX-STRAP conjugates. The peptide-drug conjugates showed no significant toxicity to the HEK-293 cells under the tested conditions, thereby confirming the earlier reported observation of higher uptake rates in cancerous cells."	"Electrostatics modulates the interactions of CPPs with the corresponding cell surface. Therefore, for the design of the amino acid side chain sequences, we reverse-engineered the spatial electrostatic potential distribution of the previously designed peptides with cell penetration ability. The spatial electrostatic fingerprints of the earlier designed peptides were generated as described previously. The reverse-engineered sequences with a shorter (7-mer) chain length were compared to the previous designs through multiple iterations of amino acid sequences. Their respective electrostatic profiles were used for the design of four syndiotactic, cationic, amphipathic peptides with optimal sequence selection. These syndiotactic re-engineered amphipathic peptides (STRAPs) were tested for their ability to penetrate cells and deliver a small molecule (methotrexate). The amino acid constitutions of STRAP-1, STRAP-2, STRAP-3, and STRAP-4 are the same. However, STRAP-2 is the stereochemically reversed STRAP-1; similarly, STRAP-4 is the stereochemically reversed STRAP-3. The use of LDLD and DLDL stereochemical sequences in the design of STRAPs resulted in the differential electrostatic signatures for the same amino acid sequences. The designed peptides have a higher cellular uptake in TNBC cells (MDA-MB-231) than the standard control TAT peptide. They could penetrate cells by both active and passive processes, and their activity is not reduced in biological fluids (human plasma and bovine serum). Furthermore, the delivery of MTX as STRAP-MTX conjugates helped to overcome the drug resistance of the MDA-MB-231 cells under in vitro conditions. The delivery of the STARP-4-MTX conjugate in TNBC xenograft tumors was more effective in the reduction of both the tumor size and metastasis to the lungs, liver, spleen, and lymph nodes."
REF00225	PDC_00343	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.82 &plusmn; 0.24 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	72 h	.	MTT assay	"To deliver the functional molecule into the cells, we attached an anticancer drug, methotrexate (MTX), to the N-terminus of STRAPs. The peptides were tested for their capability to deliver the active drug molecule in breast and cervical cancer cells. MDA-MB-231 and HeLa cells were treated with varying concentrations of MTX and STRAP-MTX conjugates for 72 h. Cell viability was assessed using the MTT assay. The cytotoxicity of MTX increased when delivered as peptide-MTX conjugates to the cells. This resulted in an overall reduction in the inhibitory concentration cytotoxic to 50% of cells (IC50) for MTX. The MTX resistance for MDA-MB-231 cells is well-established. The IC50 for MTX in MDA-MB-231 cells was minimum when delivered as a STRAP-4-MTX conjugate. Similar lowering of IC50 values in HeLa cells was observed. We also treated HEK-293 cells with MTX-STRAP conjugates. The peptide-drug conjugates showed no significant toxicity to the HEK-293 cells under the tested conditions, thereby confirming the earlier reported observation of higher uptake rates in cancerous cells."	"Electrostatics modulates the interactions of CPPs with the corresponding cell surface. Therefore, for the design of the amino acid side chain sequences, we reverse-engineered the spatial electrostatic potential distribution of the previously designed peptides with cell penetration ability. The spatial electrostatic fingerprints of the earlier designed peptides were generated as described previously. The reverse-engineered sequences with a shorter (7-mer) chain length were compared to the previous designs through multiple iterations of amino acid sequences. Their respective electrostatic profiles were used for the design of four syndiotactic, cationic, amphipathic peptides with optimal sequence selection. These syndiotactic re-engineered amphipathic peptides (STRAPs) were tested for their ability to penetrate cells and deliver a small molecule (methotrexate). The amino acid constitutions of STRAP-1, STRAP-2, STRAP-3, and STRAP-4 are the same. However, STRAP-2 is the stereochemically reversed STRAP-1; similarly, STRAP-4 is the stereochemically reversed STRAP-3. The use of LDLD and DLDL stereochemical sequences in the design of STRAPs resulted in the differential electrostatic signatures for the same amino acid sequences. The designed peptides have a higher cellular uptake in TNBC cells (MDA-MB-231) than the standard control TAT peptide. They could penetrate cells by both active and passive processes, and their activity is not reduced in biological fluids (human plasma and bovine serum). Furthermore, the delivery of MTX as STRAP-MTX conjugates helped to overcome the drug resistance of the MDA-MB-231 cells under in vitro conditions. The delivery of the STARP-4-MTX conjugate in TNBC xenograft tumors was more effective in the reduction of both the tumor size and metastasis to the lungs, liver, spleen, and lymph nodes."
REF00225	PDC_00344	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.79 &plusmn; 0.31 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	72 h	.	MTT assay	"To deliver the functional molecule into the cells, we attached an anticancer drug, methotrexate (MTX), to the N-terminus of STRAPs. The peptides were tested for their capability to deliver the active drug molecule in breast and cervical cancer cells. MDA-MB-231 and HeLa cells were treated with varying concentrations of MTX and STRAP-MTX conjugates for 72 h. Cell viability was assessed using the MTT assay. The cytotoxicity of MTX increased when delivered as peptide-MTX conjugates to the cells. This resulted in an overall reduction in the inhibitory concentration cytotoxic to 50% of cells (IC50) for MTX. The MTX resistance for MDA-MB-231 cells is well-established. The IC50 for MTX in MDA-MB-231 cells was minimum when delivered as a STRAP-4-MTX conjugate. Similar lowering of IC50 values in HeLa cells was observed. We also treated HEK-293 cells with MTX-STRAP conjugates. The peptide-drug conjugates showed no significant toxicity to the HEK-293 cells under the tested conditions, thereby confirming the earlier reported observation of higher uptake rates in cancerous cells."	"Electrostatics modulates the interactions of CPPs with the corresponding cell surface. Therefore, for the design of the amino acid side chain sequences, we reverse-engineered the spatial electrostatic potential distribution of the previously designed peptides with cell penetration ability. The spatial electrostatic fingerprints of the earlier designed peptides were generated as described previously. The reverse-engineered sequences with a shorter (7-mer) chain length were compared to the previous designs through multiple iterations of amino acid sequences. Their respective electrostatic profiles were used for the design of four syndiotactic, cationic, amphipathic peptides with optimal sequence selection. These syndiotactic re-engineered amphipathic peptides (STRAPs) were tested for their ability to penetrate cells and deliver a small molecule (methotrexate). The amino acid constitutions of STRAP-1, STRAP-2, STRAP-3, and STRAP-4 are the same. However, STRAP-2 is the stereochemically reversed STRAP-1; similarly, STRAP-4 is the stereochemically reversed STRAP-3. The use of LDLD and DLDL stereochemical sequences in the design of STRAPs resulted in the differential electrostatic signatures for the same amino acid sequences. The designed peptides have a higher cellular uptake in TNBC cells (MDA-MB-231) than the standard control TAT peptide. They could penetrate cells by both active and passive processes, and their activity is not reduced in biological fluids (human plasma and bovine serum). Furthermore, the delivery of MTX as STRAP-MTX conjugates helped to overcome the drug resistance of the MDA-MB-231 cells under in vitro conditions. The delivery of the STARP-4-MTX conjugate in TNBC xenograft tumors was more effective in the reduction of both the tumor size and metastasis to the lungs, liver, spleen, and lymph nodes."
REF00225	PDC_00345	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.34 &plusmn; 0.19 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	72 h	.	MTT assay	"To deliver the functional molecule into the cells, we attached an anticancer drug, methotrexate (MTX), to the N-terminus of STRAPs. The peptides were tested for their capability to deliver the active drug molecule in breast and cervical cancer cells. MDA-MB-231 and HeLa cells were treated with varying concentrations of MTX and STRAP-MTX conjugates for 72 h. Cell viability was assessed using the MTT assay. The cytotoxicity of MTX increased when delivered as peptide-MTX conjugates to the cells. This resulted in an overall reduction in the inhibitory concentration cytotoxic to 50% of cells (IC50) for MTX. The MTX resistance for MDA-MB-231 cells is well-established. The IC50 for MTX in MDA-MB-231 cells was minimum when delivered as a STRAP-4-MTX conjugate. Similar lowering of IC50 values in HeLa cells was observed. We also treated HEK-293 cells with MTX-STRAP conjugates. The peptide-drug conjugates showed no significant toxicity to the HEK-293 cells under the tested conditions, thereby confirming the earlier reported observation of higher uptake rates in cancerous cells."	"Electrostatics modulates the interactions of CPPs with the corresponding cell surface. Therefore, for the design of the amino acid side chain sequences, we reverse-engineered the spatial electrostatic potential distribution of the previously designed peptides with cell penetration ability. The spatial electrostatic fingerprints of the earlier designed peptides were generated as described previously. The reverse-engineered sequences with a shorter (7-mer) chain length were compared to the previous designs through multiple iterations of amino acid sequences. Their respective electrostatic profiles were used for the design of four syndiotactic, cationic, amphipathic peptides with optimal sequence selection. These syndiotactic re-engineered amphipathic peptides (STRAPs) were tested for their ability to penetrate cells and deliver a small molecule (methotrexate). The amino acid constitutions of STRAP-1, STRAP-2, STRAP-3, and STRAP-4 are the same. However, STRAP-2 is the stereochemically reversed STRAP-1; similarly, STRAP-4 is the stereochemically reversed STRAP-3. The use of LDLD and DLDL stereochemical sequences in the design of STRAPs resulted in the differential electrostatic signatures for the same amino acid sequences. The designed peptides have a higher cellular uptake in TNBC cells (MDA-MB-231) than the standard control TAT peptide. They could penetrate cells by both active and passive processes, and their activity is not reduced in biological fluids (human plasma and bovine serum). Furthermore, the delivery of MTX as STRAP-MTX conjugates helped to overcome the drug resistance of the MDA-MB-231 cells under in vitro conditions. The delivery of the STARP-4-MTX conjugate in TNBC xenograft tumors was more effective in the reduction of both the tumor size and metastasis to the lungs, liver, spleen, and lymph nodes."
REF00225	PDC_00342	Cervical cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.63 &plusmn; 0.28 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	.	MTT assay	"To deliver the functional molecule into the cells, we attached an anticancer drug, methotrexate (MTX), to the N-terminus of STRAPs. The peptides were tested for their capability to deliver the active drug molecule in breast and cervical cancer cells. MDA-MB-231 and HeLa cells were treated with varying concentrations of MTX and STRAP-MTX conjugates for 72 h. Cell viability was assessed using the MTT assay. The cytotoxicity of MTX increased when delivered as peptide-MTX conjugates to the cells. This resulted in an overall reduction in the inhibitory concentration cytotoxic to 50% of cells (IC50) for MTX. The MTX resistance for MDA-MB-231 cells is well-established. The IC50 for MTX in MDA-MB-231 cells was minimum when delivered as a STRAP-4-MTX conjugate. Similar lowering of IC50 values in HeLa cells was observed. We also treated HEK-293 cells with MTX-STRAP conjugates. The peptide-drug conjugates showed no significant toxicity to the HEK-293 cells under the tested conditions, thereby confirming the earlier reported observation of higher uptake rates in cancerous cells."	"Electrostatics modulates the interactions of CPPs with the corresponding cell surface. Therefore, for the design of the amino acid side chain sequences, we reverse-engineered the spatial electrostatic potential distribution of the previously designed peptides with cell penetration ability. The spatial electrostatic fingerprints of the earlier designed peptides were generated as described previously. The reverse-engineered sequences with a shorter (7-mer) chain length were compared to the previous designs through multiple iterations of amino acid sequences. Their respective electrostatic profiles were used for the design of four syndiotactic, cationic, amphipathic peptides with optimal sequence selection. These syndiotactic re-engineered amphipathic peptides (STRAPs) were tested for their ability to penetrate cells and deliver a small molecule (methotrexate). The amino acid constitutions of STRAP-1, STRAP-2, STRAP-3, and STRAP-4 are the same. However, STRAP-2 is the stereochemically reversed STRAP-1; similarly, STRAP-4 is the stereochemically reversed STRAP-3. The use of LDLD and DLDL stereochemical sequences in the design of STRAPs resulted in the differential electrostatic signatures for the same amino acid sequences. The designed peptides have a higher cellular uptake in TNBC cells (MDA-MB-231) than the standard control TAT peptide. They could penetrate cells by both active and passive processes, and their activity is not reduced in biological fluids (human plasma and bovine serum). Furthermore, the delivery of MTX as STRAP-MTX conjugates helped to overcome the drug resistance of the MDA-MB-231 cells under in vitro conditions. The delivery of the STARP-4-MTX conjugate in TNBC xenograft tumors was more effective in the reduction of both the tumor size and metastasis to the lungs, liver, spleen, and lymph nodes."
REF00225	PDC_00343	Cervical cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	11.8 &plusmn; 2.28 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	.	MTT assay	"To deliver the functional molecule into the cells, we attached an anticancer drug, methotrexate (MTX), to the N-terminus of STRAPs. The peptides were tested for their capability to deliver the active drug molecule in breast and cervical cancer cells. MDA-MB-231 and HeLa cells were treated with varying concentrations of MTX and STRAP-MTX conjugates for 72 h. Cell viability was assessed using the MTT assay. The cytotoxicity of MTX increased when delivered as peptide-MTX conjugates to the cells. This resulted in an overall reduction in the inhibitory concentration cytotoxic to 50% of cells (IC50) for MTX. The MTX resistance for MDA-MB-231 cells is well-established. The IC50 for MTX in MDA-MB-231 cells was minimum when delivered as a STRAP-4-MTX conjugate. Similar lowering of IC50 values in HeLa cells was observed. We also treated HEK-293 cells with MTX-STRAP conjugates. The peptide-drug conjugates showed no significant toxicity to the HEK-293 cells under the tested conditions, thereby confirming the earlier reported observation of higher uptake rates in cancerous cells."	"Electrostatics modulates the interactions of CPPs with the corresponding cell surface. Therefore, for the design of the amino acid side chain sequences, we reverse-engineered the spatial electrostatic potential distribution of the previously designed peptides with cell penetration ability. The spatial electrostatic fingerprints of the earlier designed peptides were generated as described previously. The reverse-engineered sequences with a shorter (7-mer) chain length were compared to the previous designs through multiple iterations of amino acid sequences. Their respective electrostatic profiles were used for the design of four syndiotactic, cationic, amphipathic peptides with optimal sequence selection. These syndiotactic re-engineered amphipathic peptides (STRAPs) were tested for their ability to penetrate cells and deliver a small molecule (methotrexate). The amino acid constitutions of STRAP-1, STRAP-2, STRAP-3, and STRAP-4 are the same. However, STRAP-2 is the stereochemically reversed STRAP-1; similarly, STRAP-4 is the stereochemically reversed STRAP-3. The use of LDLD and DLDL stereochemical sequences in the design of STRAPs resulted in the differential electrostatic signatures for the same amino acid sequences. The designed peptides have a higher cellular uptake in TNBC cells (MDA-MB-231) than the standard control TAT peptide. They could penetrate cells by both active and passive processes, and their activity is not reduced in biological fluids (human plasma and bovine serum). Furthermore, the delivery of MTX as STRAP-MTX conjugates helped to overcome the drug resistance of the MDA-MB-231 cells under in vitro conditions. The delivery of the STARP-4-MTX conjugate in TNBC xenograft tumors was more effective in the reduction of both the tumor size and metastasis to the lungs, liver, spleen, and lymph nodes."
REF00225	PDC_00344	Cervical cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.22 &plusmn; 0.18 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	.	MTT assay	"To deliver the functional molecule into the cells, we attached an anticancer drug, methotrexate (MTX), to the N-terminus of STRAPs. The peptides were tested for their capability to deliver the active drug molecule in breast and cervical cancer cells. MDA-MB-231 and HeLa cells were treated with varying concentrations of MTX and STRAP-MTX conjugates for 72 h. Cell viability was assessed using the MTT assay. The cytotoxicity of MTX increased when delivered as peptide-MTX conjugates to the cells. This resulted in an overall reduction in the inhibitory concentration cytotoxic to 50% of cells (IC50) for MTX. The MTX resistance for MDA-MB-231 cells is well-established. The IC50 for MTX in MDA-MB-231 cells was minimum when delivered as a STRAP-4-MTX conjugate. Similar lowering of IC50 values in HeLa cells was observed. We also treated HEK-293 cells with MTX-STRAP conjugates. The peptide-drug conjugates showed no significant toxicity to the HEK-293 cells under the tested conditions, thereby confirming the earlier reported observation of higher uptake rates in cancerous cells."	"Electrostatics modulates the interactions of CPPs with the corresponding cell surface. Therefore, for the design of the amino acid side chain sequences, we reverse-engineered the spatial electrostatic potential distribution of the previously designed peptides with cell penetration ability. The spatial electrostatic fingerprints of the earlier designed peptides were generated as described previously. The reverse-engineered sequences with a shorter (7-mer) chain length were compared to the previous designs through multiple iterations of amino acid sequences. Their respective electrostatic profiles were used for the design of four syndiotactic, cationic, amphipathic peptides with optimal sequence selection. These syndiotactic re-engineered amphipathic peptides (STRAPs) were tested for their ability to penetrate cells and deliver a small molecule (methotrexate). The amino acid constitutions of STRAP-1, STRAP-2, STRAP-3, and STRAP-4 are the same. However, STRAP-2 is the stereochemically reversed STRAP-1; similarly, STRAP-4 is the stereochemically reversed STRAP-3. The use of LDLD and DLDL stereochemical sequences in the design of STRAPs resulted in the differential electrostatic signatures for the same amino acid sequences. The designed peptides have a higher cellular uptake in TNBC cells (MDA-MB-231) than the standard control TAT peptide. They could penetrate cells by both active and passive processes, and their activity is not reduced in biological fluids (human plasma and bovine serum). Furthermore, the delivery of MTX as STRAP-MTX conjugates helped to overcome the drug resistance of the MDA-MB-231 cells under in vitro conditions. The delivery of the STARP-4-MTX conjugate in TNBC xenograft tumors was more effective in the reduction of both the tumor size and metastasis to the lungs, liver, spleen, and lymph nodes."
REF00225	PDC_00345	Cervical cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.01 &plusmn; 0.22 &micro;M	&micro;M	.	.	.	.	Endocervical adenocarcinoma	HeLa cell	.	.	72 h	.	MTT assay	"To deliver the functional molecule into the cells, we attached an anticancer drug, methotrexate (MTX), to the N-terminus of STRAPs. The peptides were tested for their capability to deliver the active drug molecule in breast and cervical cancer cells. MDA-MB-231 and HeLa cells were treated with varying concentrations of MTX and STRAP-MTX conjugates for 72 h. Cell viability was assessed using the MTT assay. The cytotoxicity of MTX increased when delivered as peptide-MTX conjugates to the cells. This resulted in an overall reduction in the inhibitory concentration cytotoxic to 50% of cells (IC50) for MTX. The MTX resistance for MDA-MB-231 cells is well-established. The IC50 for MTX in MDA-MB-231 cells was minimum when delivered as a STRAP-4-MTX conjugate. Similar lowering of IC50 values in HeLa cells was observed. We also treated HEK-293 cells with MTX-STRAP conjugates. The peptide-drug conjugates showed no significant toxicity to the HEK-293 cells under the tested conditions, thereby confirming the earlier reported observation of higher uptake rates in cancerous cells."	"Electrostatics modulates the interactions of CPPs with the corresponding cell surface. Therefore, for the design of the amino acid side chain sequences, we reverse-engineered the spatial electrostatic potential distribution of the previously designed peptides with cell penetration ability. The spatial electrostatic fingerprints of the earlier designed peptides were generated as described previously. The reverse-engineered sequences with a shorter (7-mer) chain length were compared to the previous designs through multiple iterations of amino acid sequences. Their respective electrostatic profiles were used for the design of four syndiotactic, cationic, amphipathic peptides with optimal sequence selection. These syndiotactic re-engineered amphipathic peptides (STRAPs) were tested for their ability to penetrate cells and deliver a small molecule (methotrexate). The amino acid constitutions of STRAP-1, STRAP-2, STRAP-3, and STRAP-4 are the same. However, STRAP-2 is the stereochemically reversed STRAP-1; similarly, STRAP-4 is the stereochemically reversed STRAP-3. The use of LDLD and DLDL stereochemical sequences in the design of STRAPs resulted in the differential electrostatic signatures for the same amino acid sequences. The designed peptides have a higher cellular uptake in TNBC cells (MDA-MB-231) than the standard control TAT peptide. They could penetrate cells by both active and passive processes, and their activity is not reduced in biological fluids (human plasma and bovine serum). Furthermore, the delivery of MTX as STRAP-MTX conjugates helped to overcome the drug resistance of the MDA-MB-231 cells under in vitro conditions. The delivery of the STARP-4-MTX conjugate in TNBC xenograft tumors was more effective in the reduction of both the tumor size and metastasis to the lungs, liver, spleen, and lymph nodes."
REF00225	PDC_00342	Renal cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Normal	HEK293 cell	.	.	72 h	.	MTT assay	"To deliver the functional molecule into the cells, we attached an anticancer drug, methotrexate (MTX), to the N-terminus of STRAPs. The peptides were tested for their capability to deliver the active drug molecule in breast and cervical cancer cells. MDA-MB-231 and HeLa cells were treated with varying concentrations of MTX and STRAP-MTX conjugates for 72 h. Cell viability was assessed using the MTT assay. The cytotoxicity of MTX increased when delivered as peptide-MTX conjugates to the cells. This resulted in an overall reduction in the inhibitory concentration cytotoxic to 50% of cells (IC50) for MTX. The MTX resistance for MDA-MB-231 cells is well-established. The IC50 for MTX in MDA-MB-231 cells was minimum when delivered as a STRAP-4-MTX conjugate. Similar lowering of IC50 values in HeLa cells was observed. We also treated HEK-293 cells with MTX-STRAP conjugates. The peptide-drug conjugates showed no significant toxicity to the HEK-293 cells under the tested conditions, thereby confirming the earlier reported observation of higher uptake rates in cancerous cells."	"Electrostatics modulates the interactions of CPPs with the corresponding cell surface. Therefore, for the design of the amino acid side chain sequences, we reverse-engineered the spatial electrostatic potential distribution of the previously designed peptides with cell penetration ability. The spatial electrostatic fingerprints of the earlier designed peptides were generated as described previously. The reverse-engineered sequences with a shorter (7-mer) chain length were compared to the previous designs through multiple iterations of amino acid sequences. Their respective electrostatic profiles were used for the design of four syndiotactic, cationic, amphipathic peptides with optimal sequence selection. These syndiotactic re-engineered amphipathic peptides (STRAPs) were tested for their ability to penetrate cells and deliver a small molecule (methotrexate). The amino acid constitutions of STRAP-1, STRAP-2, STRAP-3, and STRAP-4 are the same. However, STRAP-2 is the stereochemically reversed STRAP-1; similarly, STRAP-4 is the stereochemically reversed STRAP-3. The use of LDLD and DLDL stereochemical sequences in the design of STRAPs resulted in the differential electrostatic signatures for the same amino acid sequences. The designed peptides have a higher cellular uptake in TNBC cells (MDA-MB-231) than the standard control TAT peptide. They could penetrate cells by both active and passive processes, and their activity is not reduced in biological fluids (human plasma and bovine serum). Furthermore, the delivery of MTX as STRAP-MTX conjugates helped to overcome the drug resistance of the MDA-MB-231 cells under in vitro conditions. The delivery of the STARP-4-MTX conjugate in TNBC xenograft tumors was more effective in the reduction of both the tumor size and metastasis to the lungs, liver, spleen, and lymph nodes."
REF00225	PDC_00343	Renal cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Normal	HEK293 cell	.	.	72 h	.	MTT assay	"To deliver the functional molecule into the cells, we attached an anticancer drug, methotrexate (MTX), to the N-terminus of STRAPs. The peptides were tested for their capability to deliver the active drug molecule in breast and cervical cancer cells. MDA-MB-231 and HeLa cells were treated with varying concentrations of MTX and STRAP-MTX conjugates for 72 h. Cell viability was assessed using the MTT assay. The cytotoxicity of MTX increased when delivered as peptide-MTX conjugates to the cells. This resulted in an overall reduction in the inhibitory concentration cytotoxic to 50% of cells (IC50) for MTX. The MTX resistance for MDA-MB-231 cells is well-established. The IC50 for MTX in MDA-MB-231 cells was minimum when delivered as a STRAP-4-MTX conjugate. Similar lowering of IC50 values in HeLa cells was observed. We also treated HEK-293 cells with MTX-STRAP conjugates. The peptide-drug conjugates showed no significant toxicity to the HEK-293 cells under the tested conditions, thereby confirming the earlier reported observation of higher uptake rates in cancerous cells."	"Electrostatics modulates the interactions of CPPs with the corresponding cell surface. Therefore, for the design of the amino acid side chain sequences, we reverse-engineered the spatial electrostatic potential distribution of the previously designed peptides with cell penetration ability. The spatial electrostatic fingerprints of the earlier designed peptides were generated as described previously. The reverse-engineered sequences with a shorter (7-mer) chain length were compared to the previous designs through multiple iterations of amino acid sequences. Their respective electrostatic profiles were used for the design of four syndiotactic, cationic, amphipathic peptides with optimal sequence selection. These syndiotactic re-engineered amphipathic peptides (STRAPs) were tested for their ability to penetrate cells and deliver a small molecule (methotrexate). The amino acid constitutions of STRAP-1, STRAP-2, STRAP-3, and STRAP-4 are the same. However, STRAP-2 is the stereochemically reversed STRAP-1; similarly, STRAP-4 is the stereochemically reversed STRAP-3. The use of LDLD and DLDL stereochemical sequences in the design of STRAPs resulted in the differential electrostatic signatures for the same amino acid sequences. The designed peptides have a higher cellular uptake in TNBC cells (MDA-MB-231) than the standard control TAT peptide. They could penetrate cells by both active and passive processes, and their activity is not reduced in biological fluids (human plasma and bovine serum). Furthermore, the delivery of MTX as STRAP-MTX conjugates helped to overcome the drug resistance of the MDA-MB-231 cells under in vitro conditions. The delivery of the STARP-4-MTX conjugate in TNBC xenograft tumors was more effective in the reduction of both the tumor size and metastasis to the lungs, liver, spleen, and lymph nodes."
REF00225	PDC_00344	Renal cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Normal	HEK293 cell	.	.	72 h	.	MTT assay	"To deliver the functional molecule into the cells, we attached an anticancer drug, methotrexate (MTX), to the N-terminus of STRAPs. The peptides were tested for their capability to deliver the active drug molecule in breast and cervical cancer cells. MDA-MB-231 and HeLa cells were treated with varying concentrations of MTX and STRAP-MTX conjugates for 72 h. Cell viability was assessed using the MTT assay. The cytotoxicity of MTX increased when delivered as peptide-MTX conjugates to the cells. This resulted in an overall reduction in the inhibitory concentration cytotoxic to 50% of cells (IC50) for MTX. The MTX resistance for MDA-MB-231 cells is well-established. The IC50 for MTX in MDA-MB-231 cells was minimum when delivered as a STRAP-4-MTX conjugate. Similar lowering of IC50 values in HeLa cells was observed. We also treated HEK-293 cells with MTX-STRAP conjugates. The peptide-drug conjugates showed no significant toxicity to the HEK-293 cells under the tested conditions, thereby confirming the earlier reported observation of higher uptake rates in cancerous cells."	"Electrostatics modulates the interactions of CPPs with the corresponding cell surface. Therefore, for the design of the amino acid side chain sequences, we reverse-engineered the spatial electrostatic potential distribution of the previously designed peptides with cell penetration ability. The spatial electrostatic fingerprints of the earlier designed peptides were generated as described previously. The reverse-engineered sequences with a shorter (7-mer) chain length were compared to the previous designs through multiple iterations of amino acid sequences. Their respective electrostatic profiles were used for the design of four syndiotactic, cationic, amphipathic peptides with optimal sequence selection. These syndiotactic re-engineered amphipathic peptides (STRAPs) were tested for their ability to penetrate cells and deliver a small molecule (methotrexate). The amino acid constitutions of STRAP-1, STRAP-2, STRAP-3, and STRAP-4 are the same. However, STRAP-2 is the stereochemically reversed STRAP-1; similarly, STRAP-4 is the stereochemically reversed STRAP-3. The use of LDLD and DLDL stereochemical sequences in the design of STRAPs resulted in the differential electrostatic signatures for the same amino acid sequences. The designed peptides have a higher cellular uptake in TNBC cells (MDA-MB-231) than the standard control TAT peptide. They could penetrate cells by both active and passive processes, and their activity is not reduced in biological fluids (human plasma and bovine serum). Furthermore, the delivery of MTX as STRAP-MTX conjugates helped to overcome the drug resistance of the MDA-MB-231 cells under in vitro conditions. The delivery of the STARP-4-MTX conjugate in TNBC xenograft tumors was more effective in the reduction of both the tumor size and metastasis to the lungs, liver, spleen, and lymph nodes."
REF00225	PDC_00345	Renal cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	Normal	HEK293 cell	.	.	72 h	.	MTT assay	"To deliver the functional molecule into the cells, we attached an anticancer drug, methotrexate (MTX), to the N-terminus of STRAPs. The peptides were tested for their capability to deliver the active drug molecule in breast and cervical cancer cells. MDA-MB-231 and HeLa cells were treated with varying concentrations of MTX and STRAP-MTX conjugates for 72 h. Cell viability was assessed using the MTT assay. The cytotoxicity of MTX increased when delivered as peptide-MTX conjugates to the cells. This resulted in an overall reduction in the inhibitory concentration cytotoxic to 50% of cells (IC50) for MTX. The MTX resistance for MDA-MB-231 cells is well-established. The IC50 for MTX in MDA-MB-231 cells was minimum when delivered as a STRAP-4-MTX conjugate. Similar lowering of IC50 values in HeLa cells was observed. We also treated HEK-293 cells with MTX-STRAP conjugates. The peptide-drug conjugates showed no significant toxicity to the HEK-293 cells under the tested conditions, thereby confirming the earlier reported observation of higher uptake rates in cancerous cells."	"Electrostatics modulates the interactions of CPPs with the corresponding cell surface. Therefore, for the design of the amino acid side chain sequences, we reverse-engineered the spatial electrostatic potential distribution of the previously designed peptides with cell penetration ability. The spatial electrostatic fingerprints of the earlier designed peptides were generated as described previously. The reverse-engineered sequences with a shorter (7-mer) chain length were compared to the previous designs through multiple iterations of amino acid sequences. Their respective electrostatic profiles were used for the design of four syndiotactic, cationic, amphipathic peptides with optimal sequence selection. These syndiotactic re-engineered amphipathic peptides (STRAPs) were tested for their ability to penetrate cells and deliver a small molecule (methotrexate). The amino acid constitutions of STRAP-1, STRAP-2, STRAP-3, and STRAP-4 are the same. However, STRAP-2 is the stereochemically reversed STRAP-1; similarly, STRAP-4 is the stereochemically reversed STRAP-3. The use of LDLD and DLDL stereochemical sequences in the design of STRAPs resulted in the differential electrostatic signatures for the same amino acid sequences. The designed peptides have a higher cellular uptake in TNBC cells (MDA-MB-231) than the standard control TAT peptide. They could penetrate cells by both active and passive processes, and their activity is not reduced in biological fluids (human plasma and bovine serum). Furthermore, the delivery of MTX as STRAP-MTX conjugates helped to overcome the drug resistance of the MDA-MB-231 cells under in vitro conditions. The delivery of the STARP-4-MTX conjugate in TNBC xenograft tumors was more effective in the reduction of both the tumor size and metastasis to the lungs, liver, spleen, and lymph nodes."
REF00223	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	31% (18-7)	%	NCT01897714	The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.	Phase 1/2	Patients with multiple myeloma.	.	.	.	.	27.9 months	.	.	"Forty-five patients received melflufen plus dexamethasone in the phase II portion of the study. The median age was 66 years, 67% were male, the median prior therapies were 4 (range, 3-5), 67% were double refractory (PI and IMiD), 58% had received previous ASCT, 20% had International Staging System (ISS) stage 3 disease, and 44% had high-risk cytogenetics. At a median follow-up time of 27.9 months, the ORR in this cohort was 31% (95% CI: 18-47), including 11% very good partial response (VGPR). No complete responses (CRs) occurred. Interestingly, among patients whose disease was refractory to melphalan in any prior line, the ORR was 44%. The CBR was 49% (95% CI: 34-64), the median duration of response (DOR) was 8.4 months (95% CI: 4.6-9.6), and median PFS was 5.7 months (95% CI: 3.7-9.2). A recently published longer term data analysis reported that at a median 46-month follow-up, the median overall survival (OS) was 20.7 months (95% CI: 11.8-41.3)."	"Melflufen, a highly lipophilic PDC, takes a novel approach by taking advantage of increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside of tumor cells. Being highly lipophilic, melflufen does not require active transport, a process that may be defective in cancer cells and contribute to chemoresistance, but instead rapidly enters cells via passive diffusion. The lipophilic nature of melflufen also likely results in its favorable distribution to bone marrow, a fatty tissue, and the physiological component most relevant to MM. Once inside the tumor cells, melflufen is rapidly hydrolyzed by aminopeptidases, enzymes that are found in normal cells but are overexpressed in MM and upon which cancer cells are particularly dependent. This hydrolysis releases potent alkylating agents - most notably melphalan and des-ethyl melflufen - within the cells. Aminopeptidase-driven release of these hydrophilic molecules, which cannot readily diffuse out, thereby results in intracellular trapping. Leveraging high tumor cell aminopeptidase concentrations to rapidly drive intracellular alkylating agent release may provide a safety advantage over alkylators, such as melphalan, which lack such a mechanism for tumor cell targeting, particularly in tumors with an aggressive phenotype."
REF00223	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	29% (22-7)	%	NCT02963493	"This study will evaluate melflufen in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma in whose disease is refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. All patients in the study will be treated with melflufen on Day 1 and dexamethasone on Days 1, 8, 15 and 22 of each 28-day cycle."	Phase 2	.	.	.	.	.	14 months	.	.	"Extensive subgroup analyses have been carried out using O-12-M1 and HORIZON data. In HORIZON, patients with triple-refractory disease and those with disease refractory to anti-CD38 mAbs in the last line had efficacy outcomes similar to those in the overall patient population. Patients with MM refractory to anti-CD38 mAbs in the last line (n = 63) had better response (ORR 35% versus 31%), median PFS (4.6 versus 3.4 months) and OS (15.4 versus 9.3 months) than patients in the MAMMOTH trial treated with conventional chemotherapy (n = 275). Baseline characteristics were similar in these two trials, except that in HORIZON, patients were more heavily pretreated (median 5 versus 4 therapies). Among patients in HORIZON whose disease was alkylator-refractory in any prior line (n = 92), the ORR was 21% and median PFS was 3.8 months. None of the seven patients with melphalan-refractory disease, however, had an objective response by independent review. This contrasts with the 44% ORR observed in nine patients with melphalan-refractory disease in O-12-M1. All seven patients in HORIZON, however, were at least triple-class refractory, and none had achieved a CR in any prior line."	"Melflufen, a highly lipophilic PDC, takes a novel approach by taking advantage of increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside of tumor cells. Being highly lipophilic, melflufen does not require active transport, a process that may be defective in cancer cells and contribute to chemoresistance, but instead rapidly enters cells via passive diffusion. The lipophilic nature of melflufen also likely results in its favorable distribution to bone marrow, a fatty tissue, and the physiological component most relevant to MM. Once inside the tumor cells, melflufen is rapidly hydrolyzed by aminopeptidases, enzymes that are found in normal cells but are overexpressed in MM and upon which cancer cells are particularly dependent. This hydrolysis releases potent alkylating agents - most notably melphalan and des-ethyl melflufen - within the cells. Aminopeptidase-driven release of these hydrophilic molecules, which cannot readily diffuse out, thereby results in intracellular trapping. Leveraging high tumor cell aminopeptidase concentrations to rapidly drive intracellular alkylating agent release may provide a safety advantage over alkylators, such as melphalan, which lack such a mechanism for tumor cell targeting, particularly in tumors with an aggressive phenotype."
REF00223	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	27%	%	NCT03151811	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with RRMM following 2-4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide. Patients received either melflufen+dex or pomalidomide+dex."	Phase 3	.	.	.	.	.	15.5 months	.	.	"OCEAN randomized patients to 28-day cycles of melflufen 40 mg intravenous on day 1 plus dexamethasone 40 mg oral (days 1, 8, 15, and 22) or pomalidomide 4 mg oral (days 1-21) plus dexamethasone 40 mg oral (days 1, 8, 15, and 22). The primary objective was to compare the PFS of melflufen plus dexamethasone and pomalidomide plus dexamethasone by independent review. Secondary endpoints include comparing ORR, OS, and safety and tolerability. Notably, the OCEAN patient population and study design mirrored those of the MM-003 study to allow for the most robust comparison between melflufen and pomalidomide. Primary results of the OCEAN trial were recently published, with additional survival follow-up ongoing. In total, 495 patients were randomized (246 to the melflufen arm and 249 to the pomalidomide arm). The study met its primary endpoints, with melflufen plus dexamethasone demonstrating a superior PFS to pomalidomide plus dexamethasone (median PFS: 6.8 months vs 4.9 months; hazard ratio [HR], 0.79 [95% CI, 0.64-0.98]; P = 0.03), but OS favored pomalidomide plus dexamethasone (median OS: 19.8 months vs 25.0 months; HR, 1.10 [95% CI, 0.85-1.44]; not significant). However, additional exploratory and post-hoc analyses identified previous ASCT and age as significant prognostic factors, which is not surprising given that transplant eligibility and age are generally correlated. Patients who had not received a previous ASCT (melflufen, n = 121; pomalidomide, n = 129) had better PFS and OS with melflufen plus dexamethasone than with pomalidomide plus dexamethasone (median PFS: 9.3 months vs 4.6 months; HR, 0.59 [95% CI, 0.44-0.79]; P < 0.001; median OS: 21.6 months vs 16.5 months; HR, 0.78 [95% CI, 0.55-1.12]; not significant), while patients who had received previous ASCT (melflufen, n = 125; pomalidomide, n = 120) saw similar PFS between groups but worse OS with melflufen plus dexamethasone than with pomalidomide plus dexamethasone (median PFS: 4.4 months vs 5.2 months; HR, 1.06 [95% CI, 0.79-1.43]; not significant; median OS: 16.7 months vs 31.0 months; HR, 1.61 [95% CI, 1.09-2.40]; P = 0.02). In patients aged &ge;75, PFS was more favorable with melflufen (HR, 0.43 [95% CI, 0.24-0.76]; P = 0.003) but in patients aged <65, OS data favored pomalidomide (HR, 1.71 [95% CI, 1.09-2.69]; P = 0.02). Safety was evaluated in patients who received at least one dose of study medication (melflufen, n = 228; pomalidomide, n = 246)."	"Melflufen, a highly lipophilic PDC, takes a novel approach by taking advantage of increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside of tumor cells. Being highly lipophilic, melflufen does not require active transport, a process that may be defective in cancer cells and contribute to chemoresistance, but instead rapidly enters cells via passive diffusion. The lipophilic nature of melflufen also likely results in its favorable distribution to bone marrow, a fatty tissue, and the physiological component most relevant to MM. Once inside the tumor cells, melflufen is rapidly hydrolyzed by aminopeptidases, enzymes that are found in normal cells but are overexpressed in MM and upon which cancer cells are particularly dependent. This hydrolysis releases potent alkylating agents - most notably melphalan and des-ethyl melflufen - within the cells. Aminopeptidase-driven release of these hydrophilic molecules, which cannot readily diffuse out, thereby results in intracellular trapping. Leveraging high tumor cell aminopeptidase concentrations to rapidly drive intracellular alkylating agent release may provide a safety advantage over alkylators, such as melphalan, which lack such a mechanism for tumor cell targeting, particularly in tumors with an aggressive phenotype."
REF00223	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate (ORR)	70%	%	NCT03481556	This is an open-label Phase 1/2a study which will enroll patients that have relapsed or relapsed-refractory multiple myeloma to combination regimens of melflufen with currently approved agents. Patients will receive either melflufen+dexamethasone+bortezomib or melflufen+dexamethasone+daratumumab.	Phase 1/2	.	.	.	.	.	11.9 months	.	.	"Results for 33 patients in the melflufen/daratumumab/dexamethasone arm and 10 in the melflufen/bortezomib/dexamethasone arm have been previously reported. Patients in the daratumumab-containing arm had a median age of 64, and a median of two prior therapies. High-risk cytogenetics were present in 42%, and 61% were refractory to their last therapy. At a median treatment duration of 8.4 months, the ORR was 70%, consisting of one sCR, one CR, and ten VGPRs, and median PFS was 11.5 months. No DLTS were reported, and the most common grade &ge;3 treatment-related AEs were neutropenia (58%) and thrombocytopenia (55%). There were two fatal AEs (myeloma progression and sepsis; general physical health deterioration) of which sepsis was considered treatment related. In the melflufen/bortezomib/dexamethasone arm, the median age was 71 years, and patients had a median"	"Melflufen, a highly lipophilic PDC, takes a novel approach by taking advantage of increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside of tumor cells. Being highly lipophilic, melflufen does not require active transport, a process that may be defective in cancer cells and contribute to chemoresistance, but instead rapidly enters cells via passive diffusion. The lipophilic nature of melflufen also likely results in its favorable distribution to bone marrow, a fatty tissue, and the physiological component most relevant to MM. Once inside the tumor cells, melflufen is rapidly hydrolyzed by aminopeptidases, enzymes that are found in normal cells but are overexpressed in MM and upon which cancer cells are particularly dependent. This hydrolysis releases potent alkylating agents - most notably melphalan and des-ethyl melflufen - within the cells. Aminopeptidase-driven release of these hydrophilic molecules, which cannot readily diffuse out, thereby results in intracellular trapping. Leveraging high tumor cell aminopeptidase concentrations to rapidly drive intracellular alkylating agent release may provide a safety advantage over alkylators, such as melphalan, which lack such a mechanism for tumor cell targeting, particularly in tumors with an aggressive phenotype."
REF00223	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	5.7 months	months	NCT01897714	The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.	Phase 1/2	.	.	.	.	.	27.9 months	.	.	"Forty-five patients received melflufen plus dexamethasone in the phase II portion of the study. The median age was 66 years, 67% were male, the median prior therapies were 4 (range, 3-5), 67% were double refractory (PI and IMiD), 58% had received previous ASCT, 20% had International Staging System (ISS) stage 3 disease, and 44% had high-risk cytogenetics. At a median follow-up time of 27.9 months, the ORR in this cohort was 31% (95% CI: 18-47), including 11% very good partial response (VGPR). No complete responses (CRs) occurred. Interestingly, among patients whose disease was refractory to melphalan in any prior line, the ORR was 44%. The CBR was 49% (95% CI: 34-64), the median duration of response (DOR) was 8.4 months (95% CI: 4.6-9.6), and median PFS was 5.7 months (95% CI: 3.7-9.2). A recently published longer term data analysis reported that at a median 46-month follow-up, the median overall survival (OS) was 20.7 months (95% CI: 11.8-41.3)."	"Melflufen, a highly lipophilic PDC, takes a novel approach by taking advantage of increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside of tumor cells. Being highly lipophilic, melflufen does not require active transport, a process that may be defective in cancer cells and contribute to chemoresistance, but instead rapidly enters cells via passive diffusion. The lipophilic nature of melflufen also likely results in its favorable distribution to bone marrow, a fatty tissue, and the physiological component most relevant to MM. Once inside the tumor cells, melflufen is rapidly hydrolyzed by aminopeptidases, enzymes that are found in normal cells but are overexpressed in MM and upon which cancer cells are particularly dependent. This hydrolysis releases potent alkylating agents - most notably melphalan and des-ethyl melflufen - within the cells. Aminopeptidase-driven release of these hydrophilic molecules, which cannot readily diffuse out, thereby results in intracellular trapping. Leveraging high tumor cell aminopeptidase concentrations to rapidly drive intracellular alkylating agent release may provide a safety advantage over alkylators, such as melphalan, which lack such a mechanism for tumor cell targeting, particularly in tumors with an aggressive phenotype."
REF00223	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	4.2 months	months	NCT02963493	"This study will evaluate melflufen in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma in whose disease is refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. All patients in the study will be treated with melflufen on Day 1 and dexamethasone on Days 1, 8, 15 and 22 of each 28-day cycle."	Phase 2	.	.	.	.	.	14 months	.	.	"Extensive subgroup analyses have been carried out using O-12-M1 and HORIZON data. In HORIZON, patients with triple-refractory disease and those with disease refractory to anti-CD38 mAbs in the last line had efficacy outcomes similar to those in the overall patient population. Patients with MM refractory to anti-CD38 mAbs in the last line (n = 63) had better response (ORR 35% versus 31%), median PFS (4.6 versus 3.4 months) and OS (15.4 versus 9.3 months) than patients in the MAMMOTH trial treated with conventional chemotherapy (n = 275). Baseline characteristics were similar in these two trials, except that in HORIZON, patients were more heavily pretreated (median 5 versus 4 therapies). Among patients in HORIZON whose disease was alkylator-refractory in any prior line (n = 92), the ORR was 21% and median PFS was 3.8 months. None of the seven patients with melphalan-refractory disease, however, had an objective response by independent review. This contrasts with the 44% ORR observed in nine patients with melphalan-refractory disease in O-12-M1. All seven patients in HORIZON, however, were at least triple-class refractory, and none had achieved a CR in any prior line."	"Melflufen, a highly lipophilic PDC, takes a novel approach by taking advantage of increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside of tumor cells. Being highly lipophilic, melflufen does not require active transport, a process that may be defective in cancer cells and contribute to chemoresistance, but instead rapidly enters cells via passive diffusion. The lipophilic nature of melflufen also likely results in its favorable distribution to bone marrow, a fatty tissue, and the physiological component most relevant to MM. Once inside the tumor cells, melflufen is rapidly hydrolyzed by aminopeptidases, enzymes that are found in normal cells but are overexpressed in MM and upon which cancer cells are particularly dependent. This hydrolysis releases potent alkylating agents - most notably melphalan and des-ethyl melflufen - within the cells. Aminopeptidase-driven release of these hydrophilic molecules, which cannot readily diffuse out, thereby results in intracellular trapping. Leveraging high tumor cell aminopeptidase concentrations to rapidly drive intracellular alkylating agent release may provide a safety advantage over alkylators, such as melphalan, which lack such a mechanism for tumor cell targeting, particularly in tumors with an aggressive phenotype."
REF00223	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	6.8 months	months	NCT03151811	"This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with RRMM following 2-4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide. Patients received either melflufen+dex or pomalidomide+dex."	Phase 3	.	.	.	.	.	15.5 months	.	.	"OCEAN randomized patients to 28-day cycles of melflufen 40 mg intravenous on day 1 plus dexamethasone 40 mg oral (days 1, 8, 15, and 22) or pomalidomide 4 mg oral (days 1-21) plus dexamethasone 40 mg oral (days 1, 8, 15, and 22). The primary objective was to compare the PFS of melflufen plus dexamethasone and pomalidomide plus dexamethasone by independent review. Secondary endpoints include comparing ORR, OS, and safety and tolerability. Notably, the OCEAN patient population and study design mirrored those of the MM-003 study to allow for the most robust comparison between melflufen and pomalidomide. Primary results of the OCEAN trial were recently published, with additional survival follow-up ongoing. In total, 495 patients were randomized (246 to the melflufen arm and 249 to the pomalidomide arm). The study met its primary endpoints, with melflufen plus dexamethasone demonstrating a superior PFS to pomalidomide plus dexamethasone (median PFS: 6.8 months vs 4.9 months; hazard ratio [HR], 0.79 [95% CI, 0.64-0.98]; P = 0.03), but OS favored pomalidomide plus dexamethasone (median OS: 19.8 months vs 25.0 months; HR, 1.10 [95% CI, 0.85-1.44]; not significant). However, additional exploratory and post-hoc analyses identified previous ASCT and age as significant prognostic factors, which is not surprising given that transplant eligibility and age are generally correlated. Patients who had not received a previous ASCT (melflufen, n = 121; pomalidomide, n = 129) had better PFS and OS with melflufen plus dexamethasone than with pomalidomide plus dexamethasone (median PFS: 9.3 months vs 4.6 months; HR, 0.59 [95% CI, 0.44-0.79]; P < 0.001; median OS: 21.6 months vs 16.5 months; HR, 0.78 [95% CI, 0.55-1.12]; not significant), while patients who had received previous ASCT (melflufen, n = 125; pomalidomide, n = 120) saw similar PFS between groups but worse OS with melflufen plus dexamethasone than with pomalidomide plus dexamethasone (median PFS: 4.4 months vs 5.2 months; HR, 1.06 [95% CI, 0.79-1.43]; not significant; median OS: 16.7 months vs 31.0 months; HR, 1.61 [95% CI, 1.09-2.40]; P = 0.02). In patients aged &ge;75, PFS was more favorable with melflufen (HR, 0.43 [95% CI, 0.24-0.76]; P = 0.003) but in patients aged <65, OS data favored pomalidomide (HR, 1.71 [95% CI, 1.09-2.69]; P = 0.02). Safety was evaluated in patients who received at least one dose of study medication (melflufen, n = 228; pomalidomide, n = 246)."	"Melflufen, a highly lipophilic PDC, takes a novel approach by taking advantage of increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside of tumor cells. Being highly lipophilic, melflufen does not require active transport, a process that may be defective in cancer cells and contribute to chemoresistance, but instead rapidly enters cells via passive diffusion. The lipophilic nature of melflufen also likely results in its favorable distribution to bone marrow, a fatty tissue, and the physiological component most relevant to MM. Once inside the tumor cells, melflufen is rapidly hydrolyzed by aminopeptidases, enzymes that are found in normal cells but are overexpressed in MM and upon which cancer cells are particularly dependent. This hydrolysis releases potent alkylating agents - most notably melphalan and des-ethyl melflufen - within the cells. Aminopeptidase-driven release of these hydrophilic molecules, which cannot readily diffuse out, thereby results in intracellular trapping. Leveraging high tumor cell aminopeptidase concentrations to rapidly drive intracellular alkylating agent release may provide a safety advantage over alkylators, such as melphalan, which lack such a mechanism for tumor cell targeting, particularly in tumors with an aggressive phenotype."
REF00223	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	11.5 months	months	NCT03481556	This is an open-label Phase 1/2a study which will enroll patients that have relapsed or relapsed-refractory multiple myeloma to combination regimens of melflufen with currently approved agents. Patients will receive either melflufen+dexamethasone+bortezomib or melflufen+dexamethasone+daratumumab.	Phase 1/2	.	.	.	.	.	11.9 months	.	.	"Results for 33 patients in the melflufen/daratumumab/dexamethasone arm and 10 in the melflufen/bortezomib/dexamethasone arm have been previously reported. Patients in the daratumumab-containing arm had a median age of 64, and a median of two prior therapies. High-risk cytogenetics were present in 42%, and 61% were refractory to their last therapy. At a median treatment duration of 8.4 months, the ORR was 70%, consisting of one sCR, one CR, and ten VGPRs, and median PFS was 11.5 months. No DLTS were reported, and the most common grade &ge;3 treatment-related AEs were neutropenia (58%) and thrombocytopenia (55%). There were two fatal AEs (myeloma progression and sepsis; general physical health deterioration) of which sepsis was considered treatment related. In the melflufen/bortezomib/dexamethasone arm, the median age was 71 years, and patients had a median"	"Melflufen, a highly lipophilic PDC, takes a novel approach by taking advantage of increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside of tumor cells. Being highly lipophilic, melflufen does not require active transport, a process that may be defective in cancer cells and contribute to chemoresistance, but instead rapidly enters cells via passive diffusion. The lipophilic nature of melflufen also likely results in its favorable distribution to bone marrow, a fatty tissue, and the physiological component most relevant to MM. Once inside the tumor cells, melflufen is rapidly hydrolyzed by aminopeptidases, enzymes that are found in normal cells but are overexpressed in MM and upon which cancer cells are particularly dependent. This hydrolysis releases potent alkylating agents - most notably melphalan and des-ethyl melflufen - within the cells. Aminopeptidase-driven release of these hydrophilic molecules, which cannot readily diffuse out, thereby results in intracellular trapping. Leveraging high tumor cell aminopeptidase concentrations to rapidly drive intracellular alkylating agent release may provide a safety advantage over alkylators, such as melphalan, which lack such a mechanism for tumor cell targeting, particularly in tumors with an aggressive phenotype."
REF00221	PDC_00245	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.066 &micro;g/mL	&micro;g/mL	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	.	MTT assay	"The cytotoxicity of PPP in MCF-7, HCT116, and 4T1 cells was investigated by MTT assay. The half maximal inhibitory concentration (IC50) of PPP NPs and free PTX was calculated to be 0.066 and 0.028 &mu;g/mL on MCF-7 cells, 0.044 and 0.006 &mu;g/mL on HCT116, 0.212 and 0.01 &mu;g/mL on 4T1 cells which indicated a lower cell growth inhibition ability than free PTX. The result may be owing to the extremely stable property of PPP and low legumain expression in vitro leading to incomplete release of PTX and PTP-7 (Edgington et al., 2013). Moreover, the holographic microscopy studies showed the changes in cellular morphology of MCF-7 cells after treated with PPP for 3 h. Notably, PPP led to the morphological features of apoptosis such as shrinkage, losing contact with neighboring cells and floating relative to control."	"Herein, we present a lytic peptide PTP7-drug paclitaxel conjugate assembling nanoparticles (named PPP) that can sequentially respond to dual stimuli in the tumor microenvironment, which was designed for passive tumor-targeted delivery and on-demand release of a tumor lytic peptide (PTP-7) as well as a chemotherapeutic agent of paclitaxel (PTX). To achieve this, tumor lytic peptide PTP-7 was connected with polyethylene glycol by a peptide substrate of legumain to serve as hydrophobic segments of nanoparticles to protect the peptide from enzymatic degradation. After that, PTX was connected to the amino group of the polypeptide side chain through an acid-responsive chemical bond (2-propionic-3-methylmaleic anhydride, CDM). Therefore, the nanoparticle (PPP) collapsed when it encountered the weakly acidic tumor microenvironment where PTX molecules fell off, and further triggered the cleavage of the peptide substrate by legumain that is highly expressed in tumor stroma and tumor cell surface. Moreover, PPP presents improved stability, improved drug solubility, prolonged blood circulation and significant inhibition ability on tumor growth, which gives a reasonable strategy to accurately deliver small molecule drugs and active peptides simultaneously to tumor sites."
REF00221	PDC_00245	Colon cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.044 &micro;g/mL	&micro;g/mL	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	72 h	.	MTT assay	"The cytotoxicity of PPP in MCF-7, HCT116, and 4T1 cells was investigated by MTT assay. The half maximal inhibitory concentration (IC50) of PPP NPs and free PTX was calculated to be 0.066 and 0.028 &mu;g/mL on MCF-7 cells, 0.044 and 0.006 &mu;g/mL on HCT116, 0.212 and 0.01 &mu;g/mL on 4T1 cells which indicated a lower cell growth inhibition ability than free PTX. The result may be owing to the extremely stable property of PPP and low legumain expression in vitro leading to incomplete release of PTX and PTP-7 (Edgington et al., 2013). Moreover, the holographic microscopy studies showed the changes in cellular morphology of MCF-7 cells after treated with PPP for 3 h. Notably, PPP led to the morphological features of apoptosis such as shrinkage, losing contact with neighboring cells and floating relative to control."	"Herein, we present a lytic peptide PTP7-drug paclitaxel conjugate assembling nanoparticles (named PPP) that can sequentially respond to dual stimuli in the tumor microenvironment, which was designed for passive tumor-targeted delivery and on-demand release of a tumor lytic peptide (PTP-7) as well as a chemotherapeutic agent of paclitaxel (PTX). To achieve this, tumor lytic peptide PTP-7 was connected with polyethylene glycol by a peptide substrate of legumain to serve as hydrophobic segments of nanoparticles to protect the peptide from enzymatic degradation. After that, PTX was connected to the amino group of the polypeptide side chain through an acid-responsive chemical bond (2-propionic-3-methylmaleic anhydride, CDM). Therefore, the nanoparticle (PPP) collapsed when it encountered the weakly acidic tumor microenvironment where PTX molecules fell off, and further triggered the cleavage of the peptide substrate by legumain that is highly expressed in tumor stroma and tumor cell surface. Moreover, PPP presents improved stability, improved drug solubility, prolonged blood circulation and significant inhibition ability on tumor growth, which gives a reasonable strategy to accurately deliver small molecule drugs and active peptides simultaneously to tumor sites."
REF00221	PDC_00245	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.212 &micro;g/mL	&micro;g/mL	.	.	.	.	Mammary carcinoma	4T1 cell	.	.	72 h	.	MTT assay	"The cytotoxicity of PPP in MCF-7, HCT116, and 4T1 cells was investigated by MTT assay. The half maximal inhibitory concentration (IC50) of PPP NPs and free PTX was calculated to be 0.066 and 0.028 &mu;g/mL on MCF-7 cells, 0.044 and 0.006 &mu;g/mL on HCT116, 0.212 and 0.01 &mu;g/mL on 4T1 cells which indicated a lower cell growth inhibition ability than free PTX. The result may be owing to the extremely stable property of PPP and low legumain expression in vitro leading to incomplete release of PTX and PTP-7 (Edgington et al., 2013). Moreover, the holographic microscopy studies showed the changes in cellular morphology of MCF-7 cells after treated with PPP for 3 h. Notably, PPP led to the morphological features of apoptosis such as shrinkage, losing contact with neighboring cells and floating relative to control."	"Herein, we present a lytic peptide PTP7-drug paclitaxel conjugate assembling nanoparticles (named PPP) that can sequentially respond to dual stimuli in the tumor microenvironment, which was designed for passive tumor-targeted delivery and on-demand release of a tumor lytic peptide (PTP-7) as well as a chemotherapeutic agent of paclitaxel (PTX). To achieve this, tumor lytic peptide PTP-7 was connected with polyethylene glycol by a peptide substrate of legumain to serve as hydrophobic segments of nanoparticles to protect the peptide from enzymatic degradation. After that, PTX was connected to the amino group of the polypeptide side chain through an acid-responsive chemical bond (2-propionic-3-methylmaleic anhydride, CDM). Therefore, the nanoparticle (PPP) collapsed when it encountered the weakly acidic tumor microenvironment where PTX molecules fell off, and further triggered the cleavage of the peptide substrate by legumain that is highly expressed in tumor stroma and tumor cell surface. Moreover, PPP presents improved stability, improved drug solubility, prolonged blood circulation and significant inhibition ability on tumor growth, which gives a reasonable strategy to accurately deliver small molecule drugs and active peptides simultaneously to tumor sites."
REF00219	PDC_00194	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11.18 &plusmn; 0.38 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00189	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.24 &plusmn; 1.09 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00193	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	7.48 &plusmn; 0.66 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00185	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.85 &plusmn; 0.90 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00195	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	67.88 &plusmn; 25.36 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00190	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	48.14 &plusmn; 0.47 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00186	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.67 &plusmn; 0.07 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00186	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.51 &plusmn; 0.11 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00191	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.66 &plusmn; 0.18 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00188	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.77 &plusmn; 0.08 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00192	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	41.52 &plusmn; 9.83 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00184	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00194	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	85.57 &plusmn; 24.33 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00189	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00193	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	56.19 &plusmn; 17.28 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00185	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00195	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00190	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00186	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.03 &plusmn; 1.91 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00186	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	6.44 &plusmn; 1.22 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00191	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	4.89 &plusmn; 1.08 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00188	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.15 &plusmn; 3.22 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00192	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00184	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	100 &micro;M	&micro;M	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	72 h	.	GraphPad prism assay	"To investigate the anticancer activity of the GnRH-III drug conjugates, cell viability studies have been performed on A2780 ovarian cancer and Panc-1 pancreatic cancer cells. The GnRH-R expression of these cell lines was determined by Western blot studies. In the case of the A2780 cells, a distinct band at 38 kDa could be detected which corresponds to the full-length human GnRH-R. In contrast, the signal intensity of the 38 kDa band was much lower for Panc-1 pancreatic cancer cells being in line with our previous results. Thus, the antiproliferative activity of the GnRH-drug conjugates was studied on high-GnRH-R-expressing A2780 cells and low-GnRH-R-expressing Panc-1 cells. Since the release of free Dau and PTX can be assumed, both drugs were used as controls. The cells were treated for either 24 h (Dau conjugates) or six hours (PTX compounds), followed by additional incubation with fresh growth medium until 72 h after treatment initiation. The obtained results reveal, on the one hand, that the non-cleavable linker-containing conjugates possess a reduced anticancer activity in comparison to the cleavable conjugates and, on the other hand, that the activity of the all GnRH-III-drug conjugates was substantially reduced compared to the free drug. Moreover, all compounds displayed a lower biological activity on Panc-1 cells than on A2780. In the case of the cleavable GnRH-III-Dau conjugates, the IC50 values varied between 2.85-11.18 &mu;M on A2780 cells, whereby the best activity was obtained for compound 13 (2.85 &mu;M) which contained the cathepsin B-cleavage site Val-Ala and the GnRH-III-[2His-3D-Tic-4Lys(Bu)] peptide carrier. Apart from that, the IC50 values of the cleavable PTX conjugates on A2780 cells are in the same sub-micromolar range and vary between 0.51-0.77 &mu;M, while the activity of these conjugates was approximately 10 times lower on Panc-1 cells (5.03-8.15 &mu;M)."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00194	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	16.12 &plusmn; 2.03 &micro;M	&micro;M	.	.	.	.	Normal	Normal human pituitary cell	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00189	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	11.70 &plusmn; 0.42 &micro;M	&micro;M	.	.	.	.	Normal	Normal human pituitary cell	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00193	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	17.04 &plusmn; 1.04 &micro;M	&micro;M	.	.	.	.	Normal	Normal human pituitary cell	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00185	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	24.77 &plusmn; 1.73 &micro;M	&micro;M	.	.	.	.	Normal	Normal human pituitary cell	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00195	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.70 &plusmn; 1.07 &micro;M	&micro;M	.	.	.	.	Normal	Normal human pituitary cell	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00190	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	36.29 &plusmn; 3.17 &micro;M	&micro;M	.	.	.	.	Normal	Normal human pituitary cell	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00186	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.54 &plusmn; 2.01 &micro;M	&micro;M	.	.	.	.	Normal	Normal human pituitary cell	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00186	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	18.49 &plusmn; 2.72 &micro;M	&micro;M	.	.	.	.	Normal	Normal human pituitary cell	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00191	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	9.86 &plusmn; 0.82 &micro;M	&micro;M	.	.	.	.	Normal	Normal human pituitary cell	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00188	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.82 &plusmn; 1.98 &micro;M	&micro;M	.	.	.	.	Normal	Normal human pituitary cell	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00184	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	23.43 &plusmn; 1.67 &micro;M	&micro;M	.	.	.	.	Normal	Normal human pituitary cell	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00194	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	13.66 &plusmn; 1.87 &micro;M	&micro;M	.	.	.	.	Prostate cancer	Human prostate cancer cells	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00189	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.97 &plusmn; 1.23 &micro;M	&micro;M	.	.	.	.	Prostate cancer	Human prostate cancer cells	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00193	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	15.46 &plusmn; 0.83 &micro;M	&micro;M	.	.	.	.	Prostate cancer	Human prostate cancer cells	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00185	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	20.54 &plusmn; 1.46 &micro;M	&micro;M	.	.	.	.	Prostate cancer	Human prostate cancer cells	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00195	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.61 &plusmn; 1.08 &micro;M	&micro;M	.	.	.	.	Prostate cancer	Human prostate cancer cells	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00190	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	42.67 &plusmn; 7.04 &micro;M	&micro;M	.	.	.	.	Prostate cancer	Human prostate cancer cells	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00186	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	10.65 &plusmn; 1.82 &micro;M	&micro;M	.	.	.	.	Prostate cancer	Human prostate cancer cells	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00186	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	14.88 &plusmn; 0.33 &micro;M	&micro;M	.	.	.	.	Prostate cancer	Human prostate cancer cells	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00191	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	8.47 &plusmn; 1.06 &micro;M	&micro;M	.	.	.	.	Prostate cancer	Human prostate cancer cells	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00188	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	12.73 &plusmn; 2.23 &micro;M	&micro;M	.	.	.	.	Prostate cancer	Human prostate cancer cells	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00219	PDC_00184	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	22.21 &plusmn; 0.96 &micro;M	&micro;M	.	.	.	.	Prostate cancer	Human prostate cancer cells	.	.	.	.	.	"Human pituitary and human prostate cancer tissues have been used to evaluate the binding affinities of the new GnRH-III-drug conjugates to GnRH-R. Therefore, increasing compound concentrations were applied and the displacement of radiolabeled [<sup>125</sup>I]-triptorelin from GnRH-Rs was detected. The obtained results were compared with the binding affinities of the oxime bond-linked GnRH-III-Dau conjugates (I, II). All compounds bind to the receptors with high affinities in the low nanomolar range, while GnRH unrelated peptides such as somatostatin or bombesin were not able to displace the radio-labelled triptorelin. However, in comparison to the GnRH-III-homing peptide (I), the self-immolative linker conjugate exhibited a 3- to 10-times reduced affinity to the GnRH receptors. Interestingly, most of the PTX-containing cleavable compounds possessed a slightly higher binding affinity than the corresponding Dau-equivalent, even if the targeting sequence and the cathepsin cleavage site remained the same."	"Drug delivery systems (DDS) are promising tools for targeted tumor therapy providing the selective delivery of cytotoxic drugs to malignant cells, while side-effects and systemic toxicity are reduced. In addition to monoclonal antibodies (mAb), peptide ligands with a high affinity for tumor-specific cell surface compartments (e.g., receptors) can be used as carriers for cytotoxic payloads, as they provide beneficial features such as good tissue penetration, low immunogenicity and structural simplicity which enables their cost-efficient production by chemical synthesi. Receptors for the human gonadotropin releasing hormone (GnRH-I, &lt;EHWSYGLRPG-NH2, &lt;E is pyroglutamic acid) were not only identified in the pituitary, but also in various reproductive system-related cancers, such as breast, prostate and ovarian cancers, as well as non-reproductive cancers, such as colon and lung cancer. Thus, GnRH-related peptides are promising homing devices to deliver cytotoxic drugs selectively to cancer cells. A natural isoform of GnRH-I is the sea lamprey analog GnRH-III. This weak GnRH agonist binds to GnRH receptors (GnRH-R) on cancer cells and induces, like GnRH-I, a direct antitumor activity on several cancer cell lines, but its gonadotropin releasing activity is 500-1000 times lower in vitro and in vivo. Due to the direct anticancer activity and the low endocrine effect, GnRH-III and its derivatives have been successfully used as homing devices in in vitro and in vivo experiments. Encouraged by these promising findings, we report on the synthesis and biochemical characterization of eight cleavable self-immolative linker containing GnRH-III-drug conjugates. Of particular interest was the comparison of (1) two GnRH-III targeting moieties (GnRH-III-[4Lys(Bu)] (I) and GnRH-III-[2His,3D-Tic,4Lys(Bu)] (II)), (2) two cathepsin B-cleavable dipeptidyl-PABC linkers (Val-Ala and Val-Cit) and (3) two traditional anticancer drugs with different modes of action (Dau and PTX). For a better comparison and to demonstrate the proof of concept, four corresponding non-cleavable GnRH-III-Dau and -PTX conjugates have been developed and analyzed. The 8Lys of the targeting peptide was used as the ligation site. In the case of the Dau conjugates, the amino group of the daunosamine sugar has been used for attachment to the linker, while in the case of PTX, the C2-OH group was exploited for this purpose. All synthesized GnRH-III-Dau and -PTX conjugates were studied for their anticancer activity on A2780 ovarian and Panc-1 pancreatic cancer cells. Furthermore, the release of the drug by lysosomal enzymes and the GnRH-R binding affinities of the SMDC were examined."
REF00215	PDC_00246	Zika virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	ZIKV infection	Zika virus	.	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00248	Zika virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	25.07 &plusmn; 0.05 &micro;M	&micro;M	.	.	.	.	ZIKV infection	Zika virus	21.1 h	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00314	Zika virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.08 &plusmn; 0.14 &micro;M	&micro;M	.	.	.	.	ZIKV infection	Zika virus	22.2 h	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00316	Zika virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	ZIKV infection	Zika virus	.	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00247	Zika virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	ZIKV infection	Zika virus	.	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00249	Zika virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	ZIKV infection	Zika virus	.	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00315	Zika virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	ZIKV infection	Zika virus	.	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00317	Zika virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	ZIKV infection	Zika virus	.	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00246	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	HIV Infection	Human immunodeficiency virus	.	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00248	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	33.1 &plusmn; 1.38 &micro;M	&micro;M	.	.	.	.	HIV Infection	Human immunodeficiency virus	21.1 h	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00314	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	HIV Infection	Human immunodeficiency virus	22.2 h	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00316	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	3.02 &plusmn; 0.35 &micro;M	&micro;M	.	.	.	.	HIV Infection	Human immunodeficiency virus	.	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00247	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	HIV Infection	Human immunodeficiency virus	.	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00249	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	HIV Infection	Human immunodeficiency virus	.	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00315	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	50 &micro;M	&micro;M	.	.	.	.	HIV Infection	Human immunodeficiency virus	.	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00215	PDC_00317	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	5.28 &plusmn; 1.39 &micro;M	&micro;M	.	.	.	.	HIV Infection	Human immunodeficiency virus	.	.	1 h	.	GraphPad Prism assay	"The five PPCs that successfully translocated BBB and BPB were evaluated for ZIKV inactivation in vitro, using a plaque assay. Of them, two showed significant activity, namely MP-P5 (IC50 = 25.07 &plusmn; 0.05 &mu;M, similar to activity against HIV) and PP-P1 (IC50 = 1.08 &plusmn; 0.14 &mu;M). Additionally, a treatment assay performed with MP-P5 and PP-P1 revealed that both PPCs efficiently inhibit ZIKV replication when added 1 h and 7 h post-infection. As observed for HIV, non-conjugated porphyrins did not show activity against ZIKV, reinforcing the claim that BBBpS conjugation is not only critical for BBB/BPB translocation but also for antiviral activity. On the other hand, and somewhat unexpectedly, PP-P1, shown to be inactive in vitro against HIV, emerged as the most active anti-ZIKV conjugate. As described in the literature, the light-independent mechanism of action of porphyrins is based on a direct perturbation of the viral envelope. Porphyrins interact and accumulate on the envelope lipid membrane, causing a decrease in order and a consequent phase alteration that impairs viral entry processes. Since we ensured no-light conditions and no metal cations are coordinated to the porphyrin rings of the PPCsavoiding generation of reactive oxygen speciesthe antiviral light-independent mechanism is the only plausible one. Thus, one may confidently suggest that the PP-P1 specific anti-ZIKV activity is guided by preferential interaction with the ZIKV viral envelope and/or components."	"Strategies for conjugating BBBpS to drug payloads have been actively explored over recent decades, with the number of new shuttles steadily increasing. Some recent entries, moreover, have shown to be capable not only of carrying drugs into but also removing toxins from the brain, preventing their accumulation. For our part, we have reported that peptide-porphyrin conjugates (PPCs), where a BBBpS and an antiviral porphyrin are covalently linked by an amide bond (amino and carboxyl groups in BBBpS and porphyrin, respectively) can successfully pass the BBB and act against brain-targeting viruses such as HIV. As for the BPB, the literature is scarce, with only a few described examples of peptides able to pass it. Herein, we report our results in developing new PPCs able to penetrate both BPB and BBB and act against ZIKV. The PPC production strategy, involving porphyrin (P), C- or N-terminal conjugation to a BBBpS, has been detailed in a recent publication and is illustrated in Scheme 1 and Scheme S1. In this paper we describe eight PPCs resulting from the combination of four BBBpS and two porphyrins, and their evaluation in terms of barrier crossing and anti-ZIKV activity. One of the conjugates, PP-P1, emerges as particularly effective against ZIKV, having also the ability to translocate across BPB and BBB."
REF00015	PDC_00063	Central nervous system disease	.	Revealed Based on the Cell Line Data	.	Inhinition rate	33.21 &plusmn; 3.32%	%	.	.	.	.	Glioblastoma	U87 cell	.	.	24 h	.	.	.	.
REF00015	PDC_00063	Central nervous system disease	.	Revealed Based on the Cell Line Data	.	Inhinition rate	50.24 &plusmn; 4.75%	%	.	.	.	.	Glioblastoma	U87 cell	.	.	48 h	.	.	.	.
REF00015	PDC_00064	Central nervous system disease	.	Revealed Based on the Cell Line Data	.	Inhinition rate	31.65 &plusmn; 3.28%	%	.	.	.	.	Glioblastoma	U87 cell	.	.	24 h	.	.	.	.
REF00015	PDC_00064	Central nervous system disease	.	Revealed Based on the Cell Line Data	.	Inhinition rate	73.53 &plusmn; 6.45%	%	.	.	.	.	Glioblastoma	U87 cell	.	.	48 h	.	.	.	.
REF00014	PDC_00233	Prostate cancer	.	Revealed Based on the Cell Line Data	.	Inhinition rate	14.93 &micro;M	&micro;M	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	4 h	"C4-2 cells (310<sup>5</sup>/cells/well) were seeded in 24-well plates for 24 h and then incubated with KYL-TGX, dipeptide-TGX-D1 and TGX-D1 at 37 &deg;C. After incubation for 1 h, the cells were washed with PBS and then lysed as we described before.13Drug molecules were extracted from cell lysate using a liquid-liquid extraction method.13Both KYL-TGX and dipeptide-TGX-D1 were cleaved by NaOH to form TGX-D1 during the extraction process. Concentrations of TGX-D1 in the cell lysate were quantitated using LC-MS/MS. BCAprotein assaykit (Pierce, Rockford, IL) was used to quantitate the total protein concentration of the cell lysate. Cellular uptake was normalized to the total protein content of the samples"	72 h	.	.	.	.
REF00012	PDC_00149	Glioblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	9.0 &plusmn; 1.8 nM	nM	.	.	.	.	Glioblastoma	U-87MG cell	.	.	.	.	CCK-8 assay	Cell proliferation was quantified 4 d after treatment with 5 d or 3 using CCK-8 colorimetric assays and compared to the untreated control. Metabolic activity measured by CCK-8 was validated by quantifying celldeath using Trypan Blue.	.
REF00012	PDC_00149	Glioblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	7.9 &plusmn; 0.8 nM	nM	.	.	.	.	Glioblastoma	D-270MG cell	.	.	.	.	CCK-8 assay	Cell proliferation was quantified 4 d after treatment with 5 d or 3 using CCK-8 colorimetric assays and compared to the untreated control. Metabolic activity measured by CCK-8 was validated by quantifying celldeath using Trypan Blue.	.
REF00012	PDC_00149	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	0.6 &plusmn; 0.1 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	.	.	CCK-8 assay	Cell proliferation was quantified 4 d after treatment with 5 d or 3 using CCK-8 colorimetric assays and compared to the untreated control. Metabolic activity measured by CCK-8 was validated by quantifying celldeath using Trypan Blue.	.
REF00012	PDC_00149	Ovarian cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	2.3 &plusmn; 0.5 nM	nM	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	.	.	CCK-8 assay	Cell proliferation was quantified 4 d after treatment with 5 d or 3 using CCK-8 colorimetric assays and compared to the untreated control. Metabolic activity measured by CCK-8 was validated by quantifying celldeath using Trypan Blue.	.
REF00012	PDC_00149	Pancreatic cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	1.8 &plusmn; 0.8 nM	nM	.	.	.	.	Pancreatic ductal adenocarcinoma	BxPC-3 cell	.	.	.	.	CCK-8 assay	Cell proliferation was quantified 4 d after treatment with 5 d or 3 using CCK-8 colorimetric assays and compared to the untreated control. Metabolic activity measured by CCK-8 was validated by quantifying celldeath using Trypan Blue.	.
REF00012	PDC_00149	Pancreatic cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	2.1 &plusmn; 0.2 nM	nM	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	.	.	CCK-8 assay	Cell proliferation was quantified 4 d after treatment with 5 d or 3 using CCK-8 colorimetric assays and compared to the untreated control. Metabolic activity measured by CCK-8 was validated by quantifying celldeath using Trypan Blue.	.
REF00012	PDC_00148	Glioblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	8.5 &plusmn; 3.3 nM	nM	.	.	.	.	Glioblastoma	U-87MG cell	.	.	.	.	CCK-8 assay	Cell proliferation was quantified 4 d after treatment with each compoundusing CCK-8 colorimetric assays and compared to the untreated control.	.
REF00012	PDC_00147	Glioblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	1000 nM	nM	.	.	.	.	Glioblastoma	U-87MG cell	.	.	.	.	CCK-8 assay	Cell proliferation was quantified 4 d after treatment with each compoundusing CCK-8 colorimetric assays and compared to the untreated control.	.
REF00012	PDC_00146	Glioblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	8.9 &plusmn; 1.2 nM	nM	.	.	.	.	Glioblastoma	U-87MG cell	.	.	.	.	CCK-8 assay	Cell proliferation was quantified 4 d after treatment with each compoundusing CCK-8 colorimetric assays and compared to the untreated control.	.
REF00012	PDC_00149	Glioblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.5 &plusmn; 0.2 nM	nM	.	.	.	.	Glioblastoma	U-87MG cell	.	.	.	.	CCK-8 assay	Cell proliferation was quantified 4 d after treatment with each compoundusing CCK-8 colorimetric assays and compared to the untreated control.	.
REF00012	PDC_00148	Glioblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	5.2 &plusmn; 3.6 nM	nM	.	.	.	.	Glioblastoma	U-87MG cell	.	.	.	.	CCK-8 assay	Cell proliferation was quantified 4 d after treatment with each compoundusing CCK-8 colorimetric assays and compared to the untreated control.	.
REF00012	PDC_00147	Glioblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	3.3 &plusmn; 0.2 nM	nM	.	.	.	.	Glioblastoma	U-87MG cell	.	.	.	.	CCK-8 assay	Cell proliferation was quantified 4 d after treatment with each compoundusing CCK-8 colorimetric assays and compared to the untreated control.	.
REF00012	PDC_00146	Glioblastoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	2.8 &plusmn; 0.2 nM	nM	.	.	.	.	Glioblastoma	U-87MG cell	.	.	.	.	CCK-8 assay	Cell proliferation was quantified 4 d after treatment with each compoundusing CCK-8 colorimetric assays and compared to the untreated control.	.
REF00011	PDC_00241	Prostate cancer	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	112 day	day	.	.	.	Patients with prostate cancer.	.	.	.	.	Day 1/2/3	Dose level ( mg/m<sup>2</sup>) 1.2	.	"Among the 42 patients considered to be evaluable for efficacy, there were no observations of objective response. However, 12 (28.6%) of patients had disease stabilisation. Overall, PFS was a median of 52.0 days (n1/442; censored 8; Q1, Q3: 50.0, 112.0). However, among the 12 patients with SD as best response, progression-free survival (PFS) was considerably higher: 129 days with 8 patients censored at the date of last study visit (Table 5A). Among the 16 efficacy-evaluable patients enrolled in part 2, 5 patients presented to the study with a diagnosis of hepatocellular carcinoma and had progressed on or were intolerant of sorafenib. In these 5 patients, prolonged disease stabilisation with an average PFS of 166 days (6 months) was observed (Table 5B); in patients with HCC who received more than 2 cycles of treatment, the PFS was 209 days, approaching 7.5 months"	.
REF00011	PDC_00241	Cholangiocarcinoma	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	89 day	day	.	.	.	Patients with cholangiocarcinoma cancer.	.	.	.	.	Day 1/2/3	Dose level ( mg/m<sup>2</sup>) 2.5	.	"Among the 42 patients considered to be evaluable for efficacy, there were no observations of objective response. However, 12 (28.6%) of patients had disease stabilisation. Overall, PFS was a median of 52.0 days (n1/442; censored 8; Q1, Q3: 50.0, 112.0). However, among the 12 patients with SD as best response, progression-free survival (PFS) was considerably higher: 129 days with 8 patients censored at the date of last study visit (Table 5A). Among the 16 efficacy-evaluable patients enrolled in part 2, 5 patients presented to the study with a diagnosis of hepatocellular carcinoma and had progressed on or were intolerant of sorafenib. In these 5 patients, prolonged disease stabilisation with an average PFS of 166 days (6 months) was observed (Table 5B); in patients with HCC who received more than 2 cycles of treatment, the PFS was 209 days, approaching 7.5 months"	.
REF00011	PDC_00241	Colorectal cancer	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	112 day	day	.	.	.	Patients with colorectal cancer.	.	.	.	.	Day 1/2/3	Dose level ( mg/m<sup>2</sup>) 5	.	"Among the 42 patients considered to be evaluable for efficacy, there were no observations of objective response. However, 12 (28.6%) of patients had disease stabilisation. Overall, PFS was a median of 52.0 days (n1/442; censored 8; Q1, Q3: 50.0, 112.0). However, among the 12 patients with SD as best response, progression-free survival (PFS) was considerably higher: 129 days with 8 patients censored at the date of last study visit (Table 5A). Among the 16 efficacy-evaluable patients enrolled in part 2, 5 patients presented to the study with a diagnosis of hepatocellular carcinoma and had progressed on or were intolerant of sorafenib. In these 5 patients, prolonged disease stabilisation with an average PFS of 166 days (6 months) was observed (Table 5B); in patients with HCC who received more than 2 cycles of treatment, the PFS was 209 days, approaching 7.5 months"	.
REF00011	PDC_00241	Non-small cell lung cancer	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	52 day	day	.	.	.	Patients with non-small cell lung cancer.	.	.	.	.	Day 1/2/3	Dose level ( mg/m<sup>2</sup>) 10	.	"Among the 42 patients considered to be evaluable for efficacy, there were no observations of objective response. However, 12 (28.6%) of patients had disease stabilisation. Overall, PFS was a median of 52.0 days (n1/442; censored 8; Q1, Q3: 50.0, 112.0). However, among the 12 patients with SD as best response, progression-free survival (PFS) was considerably higher: 129 days with 8 patients censored at the date of last study visit (Table 5A). Among the 16 efficacy-evaluable patients enrolled in part 2, 5 patients presented to the study with a diagnosis of hepatocellular carcinoma and had progressed on or were intolerant of sorafenib. In these 5 patients, prolonged disease stabilisation with an average PFS of 166 days (6 months) was observed (Table 5B); in patients with HCC who received more than 2 cycles of treatment, the PFS was 209 days, approaching 7.5 months"	.
REF00011	PDC_00241	Pancreatic cancer	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	57 day	day	.	.	.	Patients with pancreas cancer.	.	.	.	.	Day 1/2/3	Dose level ( mg/m<sup>2</sup>) 40	.	"Among the 42 patients considered to be evaluable for efficacy, there were no observations of objective response. However, 12 (28.6%) of patients had disease stabilisation. Overall, PFS was a median of 52.0 days (n1/442; censored 8; Q1, Q3: 50.0, 112.0). However, among the 12 patients with SD as best response, progression-free survival (PFS) was considerably higher: 129 days with 8 patients censored at the date of last study visit (Table 5A). Among the 16 efficacy-evaluable patients enrolled in part 2, 5 patients presented to the study with a diagnosis of hepatocellular carcinoma and had progressed on or were intolerant of sorafenib. In these 5 patients, prolonged disease stabilisation with an average PFS of 166 days (6 months) was observed (Table 5B); in patients with HCC who received more than 2 cycles of treatment, the PFS was 209 days, approaching 7.5 months"	.
REF00011	PDC_00241	Adenocarcinoma	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	63 day	day	.	.	.	Patients with adenocarcinoma cancer.	.	.	.	.	Day 1/2/3	Dose level ( mg/m<sup>2</sup>) 66.8	.	"Among the 42 patients considered to be evaluable for efficacy, there were no observations of objective response. However, 12 (28.6%) of patients had disease stabilisation. Overall, PFS was a median of 52.0 days (n1/442; censored 8; Q1, Q3: 50.0, 112.0). However, among the 12 patients with SD as best response, progression-free survival (PFS) was considerably higher: 129 days with 8 patients censored at the date of last study visit (Table 5A). Among the 16 efficacy-evaluable patients enrolled in part 2, 5 patients presented to the study with a diagnosis of hepatocellular carcinoma and had progressed on or were intolerant of sorafenib. In these 5 patients, prolonged disease stabilisation with an average PFS of 166 days (6 months) was observed (Table 5B); in patients with HCC who received more than 2 cycles of treatment, the PFS was 209 days, approaching 7.5 months"	.
REF00011	PDC_00241	Prostate cancer	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	119 day	day	.	.	.	Patients with prostate cancer.	.	.	.	.	Day 1/2/3	Dose level ( mg/m<sup>2</sup>) 88	.	"Among the 42 patients considered to be evaluable for efficacy, there were no observations of objective response. However, 12 (28.6%) of patients had disease stabilisation. Overall, PFS was a median of 52.0 days (n1/442; censored 8; Q1, Q3: 50.0, 112.0). However, among the 12 patients with SD as best response, progression-free survival (PFS) was considerably higher: 129 days with 8 patients censored at the date of last study visit (Table 5A). Among the 16 efficacy-evaluable patients enrolled in part 2, 5 patients presented to the study with a diagnosis of hepatocellular carcinoma and had progressed on or were intolerant of sorafenib. In these 5 patients, prolonged disease stabilisation with an average PFS of 166 days (6 months) was observed (Table 5B); in patients with HCC who received more than 2 cycles of treatment, the PFS was 209 days, approaching 7.5 months"	.
REF00011	PDC_00241	Advanced solid tumour	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	77 day	day	.	.	.	Patients with endometrial cancer.	.	.	.	.	Day 1/2/3	Dose level ( mg/m<sup>2</sup>) 40/66.8/66.8	.	"Among the 42 patients considered to be evaluable for efficacy, there were no observations of objective response. However, 12 (28.6%) of patients had disease stabilisation. Overall, PFS was a median of 52.0 days (n1/442; censored 8; Q1, Q3: 50.0, 112.0). However, among the 12 patients with SD as best response, progression-free survival (PFS) was considerably higher: 129 days with 8 patients censored at the date of last study visit (Table 5A). Among the 16 efficacy-evaluable patients enrolled in part 2, 5 patients presented to the study with a diagnosis of hepatocellular carcinoma and had progressed on or were intolerant of sorafenib. In these 5 patients, prolonged disease stabilisation with an average PFS of 166 days (6 months) was observed (Table 5B); in patients with HCC who received more than 2 cycles of treatment, the PFS was 209 days, approaching 7.5 months"	.
REF00011	PDC_00241	Hepatocellular carcinoma	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	336 day	day	.	.	.	Patients with hepatocellular cancer.	.	.	.	.	Day 1/2/3	Dose level ( mg/m<sup>2</sup>) 40/66.8/66.8	.	"Among the 42 patients considered to be evaluable for efficacy, there were no observations of objective response. However, 12 (28.6%) of patients had disease stabilisation. Overall, PFS was a median of 52.0 days (n1/442; censored 8; Q1, Q3: 50.0, 112.0). However, among the 12 patients with SD as best response, progression-free survival (PFS) was considerably higher: 129 days with 8 patients censored at the date of last study visit (Table 5A). Among the 16 efficacy-evaluable patients enrolled in part 2, 5 patients presented to the study with a diagnosis of hepatocellular carcinoma and had progressed on or were intolerant of sorafenib. In these 5 patients, prolonged disease stabilisation with an average PFS of 166 days (6 months) was observed (Table 5B); in patients with HCC who received more than 2 cycles of treatment, the PFS was 209 days, approaching 7.5 months"	.
REF00011	PDC_00241	Prostate cancer	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	121 day	day	.	.	.	Patients with prostate cancer.	.	.	.	.	Day 1/2/3	Dose level ( mg/m<sup>2</sup>) 40/66.8/66.8	.	"Among the 42 patients considered to be evaluable for efficacy, there were no observations of objective response. However, 12 (28.6%) of patients had disease stabilisation. Overall, PFS was a median of 52.0 days (n1/442; censored 8; Q1, Q3: 50.0, 112.0). However, among the 12 patients with SD as best response, progression-free survival (PFS) was considerably higher: 129 days with 8 patients censored at the date of last study visit (Table 5A). Among the 16 efficacy-evaluable patients enrolled in part 2, 5 patients presented to the study with a diagnosis of hepatocellular carcinoma and had progressed on or were intolerant of sorafenib. In these 5 patients, prolonged disease stabilisation with an average PFS of 166 days (6 months) was observed (Table 5B); in patients with HCC who received more than 2 cycles of treatment, the PFS was 209 days, approaching 7.5 months"	.
REF00011	PDC_00241	Hepatocellular carcinoma	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	133 day	day	.	.	.	Patients with hepatocellular cancer.	.	.	.	.	Day 1/2/3	Dose level ( mg/m<sup>2</sup>) 40/66.8/66.8	.	"Among the 42 patients considered to be evaluable for efficacy, there were no observations of objective response. However, 12 (28.6%) of patients had disease stabilisation. Overall, PFS was a median of 52.0 days (n1/442; censored 8; Q1, Q3: 50.0, 112.0). However, among the 12 patients with SD as best response, progression-free survival (PFS) was considerably higher: 129 days with 8 patients censored at the date of last study visit (Table 5A). Among the 16 efficacy-evaluable patients enrolled in part 2, 5 patients presented to the study with a diagnosis of hepatocellular carcinoma and had progressed on or were intolerant of sorafenib. In these 5 patients, prolonged disease stabilisation with an average PFS of 166 days (6 months) was observed (Table 5B); in patients with HCC who received more than 2 cycles of treatment, the PFS was 209 days, approaching 7.5 months"	.
REF00011	PDC_00241	Hepatocellular carcinoma	.	Identified from the Human Clinical Data	.	Progression-free survival (PFS)	277 day	day	.	.	.	Patients with hepatocellular cancer.	.	.	.	.	Day 1/2/3	Dose level ( mg/m<sup>2</sup>) 40/66.8/66.8	.	"Among the 42 patients considered to be evaluable for efficacy, there were no observations of objective response. However, 12 (28.6%) of patients had disease stabilisation. Overall, PFS was a median of 52.0 days (n1/442; censored 8; Q1, Q3: 50.0, 112.0). However, among the 12 patients with SD as best response, progression-free survival (PFS) was considerably higher: 129 days with 8 patients censored at the date of last study visit (Table 5A). Among the 16 efficacy-evaluable patients enrolled in part 2, 5 patients presented to the study with a diagnosis of hepatocellular carcinoma and had progressed on or were intolerant of sorafenib. In these 5 patients, prolonged disease stabilisation with an average PFS of 166 days (6 months) was observed (Table 5B); in patients with HCC who received more than 2 cycles of treatment, the PFS was 209 days, approaching 7.5 months"	.
REF00010	PDC_00239	lymphoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.92 &mu;M	&mu;M	.	.	.	.	Diffuse large B-cell lymphoma	DB cell	.	.	.	.	.	"Cell cycle distribution analyses were performed on melflufen treated (0.1, 0.2 and 0.4 uM) and control cells from the KM-H2 and SU-DHL-10 cell lines in which the cytotoxic activity of melflufen during the 72 h FMCA assay was calculated as 0.92, 0.22, and 0.71 uM respectively (see Table3). To minimize potential artifacts emanating from cells exiting the analyzed cell populations, e.g. due to early and/or extensive cell death, the cells were subjected to basal cell culture conditions for 40 h (preincubation) followed by 12, 24 and 48 h treatments with melflufen. Propidium iodide (PI) staining of DNA using Vindelovs technique was followed by quantitation with flow cytometry analysis. The percentage of cells in each cell cycle phase was determined with the ModFit LT software."	.
REF00010	PDC_00239	lymphoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.39 &mu;M	&mu;M	.	.	.	.	Diffuse large B-cell lymphoma germinal center B-cell type	DoHH2 cell	.	.	.	.	.	"Cell cycle distribution analyses were performed on melflufen treated (0.1, 0.2 and 0.4 uM) and control cells from the KM-H2 and SU-DHL-10 cell lines in which the cytotoxic activity of melflufen during the 72 h FMCA assay was calculated as 0.92, 0.22, and 0.71 uM respectively (see Table3). To minimize potential artifacts emanating from cells exiting the analyzed cell populations, e.g. due to early and/or extensive cell death, the cells were subjected to basal cell culture conditions for 40 h (preincubation) followed by 12, 24 and 48 h treatments with melflufen. Propidium iodide (PI) staining of DNA using Vindelovs technique was followed by quantitation with flow cytometry analysis. The percentage of cells in each cell cycle phase was determined with the ModFit LT software."	.
REF00010	PDC_00239	lymphoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.088 &mu;M	&mu;M	.	.	.	.	Hodgkin lymphoma	HDLM-2 cell	.	.	.	.	.	"Cell cycle distribution analyses were performed on melflufen treated (0.1, 0.2 and 0.4 uM) and control cells from the KM-H2 and SU-DHL-10 cell lines in which the cytotoxic activity of melflufen during the 72 h FMCA assay was calculated as 0.92, 0.22, and 0.71 uM respectively (see Table3). To minimize potential artifacts emanating from cells exiting the analyzed cell populations, e.g. due to early and/or extensive cell death, the cells were subjected to basal cell culture conditions for 40 h (preincubation) followed by 12, 24 and 48 h treatments with melflufen. Propidium iodide (PI) staining of DNA using Vindelovs technique was followed by quantitation with flow cytometry analysis. The percentage of cells in each cell cycle phase was determined with the ModFit LT software."	.
REF00010	PDC_00239	lymphoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.22 &mu;M	&mu;M	.	.	.	.	Hodgkin lymphoma	KM-H2 cell	.	.	.	.	.	"Cell cycle distribution analyses were performed on melflufen treated (0.1, 0.2 and 0.4 uM) and control cells from the KM-H2 and SU-DHL-10 cell lines in which the cytotoxic activity of melflufen during the 72 h FMCA assay was calculated as 0.92, 0.22, and 0.71 uM respectively (see Table3). To minimize potential artifacts emanating from cells exiting the analyzed cell populations, e.g. due to early and/or extensive cell death, the cells were subjected to basal cell culture conditions for 40 h (preincubation) followed by 12, 24 and 48 h treatments with melflufen. Propidium iodide (PI) staining of DNA using Vindelovs technique was followed by quantitation with flow cytometry analysis. The percentage of cells in each cell cycle phase was determined with the ModFit LT software."	.
REF00010	PDC_00239	lymphoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.73 &mu;M	&mu;M	.	.	.	.	Hodgkin lymphoma	L-428 cell	.	.	.	.	.	"Cell cycle distribution analyses were performed on melflufen treated (0.1, 0.2 and 0.4 uM) and control cells from the KM-H2 and SU-DHL-10 cell lines in which the cytotoxic activity of melflufen during the 72 h FMCA assay was calculated as 0.92, 0.22, and 0.71 uM respectively (see Table3). To minimize potential artifacts emanating from cells exiting the analyzed cell populations, e.g. due to early and/or extensive cell death, the cells were subjected to basal cell culture conditions for 40 h (preincubation) followed by 12, 24 and 48 h treatments with melflufen. Propidium iodide (PI) staining of DNA using Vindelovs technique was followed by quantitation with flow cytometry analysis. The percentage of cells in each cell cycle phase was determined with the ModFit LT software."	.
REF00010	PDC_00239	lymphoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.011 &mu;M	&mu;M	.	.	.	.	Diffuse large B-cell lymphoma	Diffuse large B-cell lymphoma cell Ly-3	.	.	.	.	.	"Cell cycle distribution analyses were performed on melflufen treated (0.1, 0.2 and 0.4 uM) and control cells from the KM-H2 and SU-DHL-10 cell lines in which the cytotoxic activity of melflufen during the 72 h FMCA assay was calculated as 0.92, 0.22, and 0.71 uM respectively (see Table3). To minimize potential artifacts emanating from cells exiting the analyzed cell populations, e.g. due to early and/or extensive cell death, the cells were subjected to basal cell culture conditions for 40 h (preincubation) followed by 12, 24 and 48 h treatments with melflufen. Propidium iodide (PI) staining of DNA using Vindelovs technique was followed by quantitation with flow cytometry analysis. The percentage of cells in each cell cycle phase was determined with the ModFit LT software."	.
REF00010	PDC_00239	lymphoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.45 &mu;M	&mu;M	.	.	.	.	Diffuse large B-cell lymphoma germinal center B-cell type	RC-K8 cell	.	.	.	.	.	"Cell cycle distribution analyses were performed on melflufen treated (0.1, 0.2 and 0.4 uM) and control cells from the KM-H2 and SU-DHL-10 cell lines in which the cytotoxic activity of melflufen during the 72 h FMCA assay was calculated as 0.92, 0.22, and 0.71 uM respectively (see Table3). To minimize potential artifacts emanating from cells exiting the analyzed cell populations, e.g. due to early and/or extensive cell death, the cells were subjected to basal cell culture conditions for 40 h (preincubation) followed by 12, 24 and 48 h treatments with melflufen. Propidium iodide (PI) staining of DNA using Vindelovs technique was followed by quantitation with flow cytometry analysis. The percentage of cells in each cell cycle phase was determined with the ModFit LT software."	.
REF00010	PDC_00239	lymphoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.42 &mu;M	&mu;M	.	.	.	.	Diffuse large B-cell lymphoma	SU-DHL-6 cell	.	.	.	.	.	"Cell cycle distribution analyses were performed on melflufen treated (0.1, 0.2 and 0.4 uM) and control cells from the KM-H2 and SU-DHL-10 cell lines in which the cytotoxic activity of melflufen during the 72 h FMCA assay was calculated as 0.92, 0.22, and 0.71 uM respectively (see Table3). To minimize potential artifacts emanating from cells exiting the analyzed cell populations, e.g. due to early and/or extensive cell death, the cells were subjected to basal cell culture conditions for 40 h (preincubation) followed by 12, 24 and 48 h treatments with melflufen. Propidium iodide (PI) staining of DNA using Vindelovs technique was followed by quantitation with flow cytometry analysis. The percentage of cells in each cell cycle phase was determined with the ModFit LT software."	.
REF00010	PDC_00239	lymphoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.71 &mu;M	&mu;M	.	.	.	.	Diffuse large B-cell lymphoma	SU-DHL-10 cell	.	.	.	.	.	"Cell cycle distribution analyses were performed on melflufen treated (0.1, 0.2 and 0.4 uM) and control cells from the KM-H2 and SU-DHL-10 cell lines in which the cytotoxic activity of melflufen during the 72 h FMCA assay was calculated as 0.92, 0.22, and 0.71 uM respectively (see Table3). To minimize potential artifacts emanating from cells exiting the analyzed cell populations, e.g. due to early and/or extensive cell death, the cells were subjected to basal cell culture conditions for 40 h (preincubation) followed by 12, 24 and 48 h treatments with melflufen. Propidium iodide (PI) staining of DNA using Vindelovs technique was followed by quantitation with flow cytometry analysis. The percentage of cells in each cell cycle phase was determined with the ModFit LT software."	.
REF00010	PDC_00239	lymphoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.52 &mu;M	&mu;M	.	.	.	.	Diffuse large B-cell lymphoma	U-2932 cell	.	.	.	.	.	"Cell cycle distribution analyses were performed on melflufen treated (0.1, 0.2 and 0.4 uM) and control cells from the KM-H2 and SU-DHL-10 cell lines in which the cytotoxic activity of melflufen during the 72 h FMCA assay was calculated as 0.92, 0.22, and 0.71 uM respectively (see Table3). To minimize potential artifacts emanating from cells exiting the analyzed cell populations, e.g. due to early and/or extensive cell death, the cells were subjected to basal cell culture conditions for 40 h (preincubation) followed by 12, 24 and 48 h treatments with melflufen. Propidium iodide (PI) staining of DNA using Vindelovs technique was followed by quantitation with flow cytometry analysis. The percentage of cells in each cell cycle phase was determined with the ModFit LT software."	.
REF00010	PDC_00239	lymphoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.12 &mu;M	&mu;M	.	.	.	.	Diffuse large B-cell lymphoma	U-2940 cell	.	.	.	.	.	"Cell cycle distribution analyses were performed on melflufen treated (0.1, 0.2 and 0.4 uM) and control cells from the KM-H2 and SU-DHL-10 cell lines in which the cytotoxic activity of melflufen during the 72 h FMCA assay was calculated as 0.92, 0.22, and 0.71 uM respectively (see Table3). To minimize potential artifacts emanating from cells exiting the analyzed cell populations, e.g. due to early and/or extensive cell death, the cells were subjected to basal cell culture conditions for 40 h (preincubation) followed by 12, 24 and 48 h treatments with melflufen. Propidium iodide (PI) staining of DNA using Vindelovs technique was followed by quantitation with flow cytometry analysis. The percentage of cells in each cell cycle phase was determined with the ModFit LT software."	.
REF00010	PDC_00239	lymphoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.077 &mu;M	&mu;M	.	.	.	.	Diffuse large B-cell lymphoma	WSU-NHL cell	.	.	.	.	.	"Cell cycle distribution analyses were performed on melflufen treated (0.1, 0.2 and 0.4 uM) and control cells from the KM-H2 and SU-DHL-10 cell lines in which the cytotoxic activity of melflufen during the 72 h FMCA assay was calculated as 0.92, 0.22, and 0.71 uM respectively (see Table3). To minimize potential artifacts emanating from cells exiting the analyzed cell populations, e.g. due to early and/or extensive cell death, the cells were subjected to basal cell culture conditions for 40 h (preincubation) followed by 12, 24 and 48 h treatments with melflufen. Propidium iodide (PI) staining of DNA using Vindelovs technique was followed by quantitation with flow cytometry analysis. The percentage of cells in each cell cycle phase was determined with the ModFit LT software."	.
REF00010	PDC_00239	lymphoma	.	Identified from the Human Clinical Data	.	Half Maximal Inhibitory Concentration (IC50)	0.078 &mu;M	&mu;M	.	.	.	.	Lymphoma	Primary human lymphoma cell	.	.	.	.	.	"The cytotoxicity of melflufen in primary human lymphoma cells, plotted as dose response curves with survival index (SI %) for each concentration tested. Sensitivity towards melflufen varied considerably (>300 fold) and the IC50range from 2.7 nM to 0.55 uM. The efficacy of melflufen corresponded to a 13- to 455-fold potency improvement (p< 0.001) compared to melphalan."	.
REF00007	PDC_00105	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	405.3 nM	nM	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	.	.
REF00007	PDC_00105	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	236.1 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	.	.	.	.	.
REF00006	PDC_00311	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	400 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	.	.	.
REF00004	PDC_00209	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	1.27 &micro;M	&micro;M	.	.	.	.	Hepatoblastoma	GPC3 positive HepG2 cell	.	.	.	.	.	"Peptides and drug-peptide conjugates were incubated with HepG2 cells for 48 hours followed by a CCK8 cytotoxicity assay. Despite the large population of the positive charges, supramolecular peptides alone demonstrated negligible cytotoxicity (Fig. S8, ESI). The drug conjugate, HCPT-MDP26-PEG showed a dose-dependent cytotoxicity with an IC50of 1.27 uM, comparable to the IC50of free HCPT at &tilde;1.3 uM (Fig. 3a). At a high drug dosage, the drug conjugate is much more potent than free HCPT."	.
REF00003	PDC_00140	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	11.4 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"The cellular uptake of doxorubicin and the conjugates in MCF-7 and HT-29 cells was determined via flow cytometry. Tumor cells were incubated with different concentrations of the drugs in the range of 0.1 and 50mfor 72h in a serum-containing medium, followed by flow cytometric analysis to determine the percentage of doxorubicin-positive cells, whereas untreated cells served as control."	.	.	.	"Doxorubicin binds with high affinity to DNA by intercalation, which leads to DNA damage and subsequent growth inhibition44,45. We performed MTT assays in order to determine the viability of the tumor cells and additionally to assess the proliferative potential of the cells after drug treatment. MCF-7 and HT-29 cells were incubated with doxorubicin and the peptide conjugates at various concentrations in the range of 0.1 and 50 &mu;mfor 72 h (in a serum-containing medium), and the results were expressed as IC50-values (Table 1)."	.
REF00003	PDC_00141	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	19 &mu;M	&mu;M	.	.	.	.	Colon cancer	HT29 cell	.	"The cellular uptake of doxorubicin and the conjugates in MCF-7 and HT-29 cells was determined via flow cytometry. Tumor cells were incubated with different concentrations of the drugs in the range of 0.1 and 50mfor 73h in a serum-containing medium, followed by flow cytometric analysis to determine the percentage of doxorubicin-positive cells, whereas untreated cells served as control."	.	.	.	"Doxorubicin binds with high affinity to DNA by intercalation, which leads to DNA damage and subsequent growth inhibition44,45. We performed MTT assays in order to determine the viability of the tumor cells and additionally to assess the proliferative potential of the cells after drug treatment. MCF-7 and HT-29 cells were incubated with doxorubicin and the peptide conjugates at various concentrations in the range of 0.1 and 50 &mu;mfor 72 h (in a serum-containing medium), and the results were expressed as IC50-values (Table 1)."	.
REF00003	PDC_00140	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	27 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"The cellular uptake of doxorubicin and the conjugates in MCF-7 and HT-29 cells was determined via flow cytometry. Tumor cells were incubated with different concentrations of the drugs in the range of 0.1 and 50mfor 72h in a serum-containing medium, followed by flow cytometric analysis to determine the percentage of doxorubicin-positive cells, whereas untreated cells served as control."	.	.	.	"Doxorubicin binds with high affinity to DNA by intercalation, which leads to DNA damage and subsequent growth inhibition44,45. We performed MTT assays in order to determine the viability of the tumor cells and additionally to assess the proliferative potential of the cells after drug treatment. MCF-7 and HT-29 cells were incubated with doxorubicin and the peptide conjugates at various concentrations in the range of 0.1 and 50 &mu;mfor 72 h (in a serum-containing medium), and the results were expressed as IC50-values (Table 1)."	.
REF00003	PDC_00141	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	24.7 &mu;M	&mu;M	.	.	.	.	Colon cancer	HT29 cell	.	"The cellular uptake of doxorubicin and the conjugates in MCF-7 and HT-29 cells was determined via flow cytometry. Tumor cells were incubated with different concentrations of the drugs in the range of 0.1 and 50mfor 73h in a serum-containing medium, followed by flow cytometric analysis to determine the percentage of doxorubicin-positive cells, whereas untreated cells served as control."	.	.	.	"Doxorubicin binds with high affinity to DNA by intercalation, which leads to DNA damage and subsequent growth inhibition44,45. We performed MTT assays in order to determine the viability of the tumor cells and additionally to assess the proliferative potential of the cells after drug treatment. MCF-7 and HT-29 cells were incubated with doxorubicin and the peptide conjugates at various concentrations in the range of 0.1 and 50 &mu;mfor 72 h (in a serum-containing medium), and the results were expressed as IC50-values (Table 1)."	.
REF00001	PDC_00041	Glioblastoma	Nude mice bearing either human glioblastoma (U87MG)/human neuroendocrine (H727) xenograft tumors.	Discovered Using Cell Line-derived Xenograft Model	.	Radiochemical purity	89%-99%	%	.	.	.	.	.	.	.	.	.	.	.	.	.
REF00001	PDC_00035	Glioblastoma	Nude mice bearing either human glioblastoma (U87MG)/human neuroendocrine (H727) xenograft tumors.	Discovered Using Cell Line-derived Xenograft Model	.	Radiochemical purity	92%-99%	%	.	.	.	.	.	.	.	.	.	.	.	.	.
REF00002	PDC_00023	Digestive system neoplasms	AR42J tumor-bearing mice model.	Obtained from the Model Organism Data	.	Tumor cell uptake rate	47%	%	.	.	.	.	.	AR42J cell	.	.	4 h	10 nM	.	"Figure 3 shows the results of cellular uptake experiments. When incubated with111In-DTPA-Asp1-octreotide, the uptake levels of radioactivity by AR42J cells were extremely low compared with those for111In-DTPA-d-Phe1-octreotide. In contrast, the uptake levels of111In-DTPA-Asp0-d-Phe1-octreotide increased in a time-dependent manner. The uptake levels of111In-DTPA-Asp0-d-Phe1-octreotide were not significantly different from those for111In-DTPA-d-Phe1-octreotide at 4h. For 111In-DTPA-Asp0-d-Phe1-octreotide, cell uptake experiments were conducted in the presence of varying concentrations of an unmodified octreotide. In Figure 4, uptake levels are shown as a percentage of the radioactivity level in the absence of the unmodified octreotide. The uptake levels of 111In-DTPA-Asp0-d-Phe1-octreotide were reduced in association with the concentration of the unmodified octreotide. The radioactivity uptake level was reduced by approximately 90% at 1 M concentration of the octreotide."	"In our previous study, d-Phe at position 1 in 111In-DTPA-d-Phe1-octreotide was replaced with Asp to minimize the change in molecular size. While the Phe3D-Trp4Lys5Thr6 sequence in octreotide is important for binding to the somatostatin receptor, the majority of octreotide derivatives with high somatostatin receptor affinity possess an N-terminal amino acid with an aromatic side chain, such as d-Phe or naphthylalanine. With these findings in mind, we designed, synthesized and evaluated not only the previously reported 111In-DTPA-Asp1-octreotide but also 111In-DTPA-Asp0-d-Phe1-octreotide, in which an Asp was incorporated between DTPA and N-terminal d-Phe in 111In-DTPA-d-Phe1-octreotide."
REF00005	PDC_00154	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	0.87 &micro;M	&micro;M	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	"To further confirm the specific endocytosis of GE11-DOX through EGFR, a competition assay was conducted[16]. As shown inFig. 5, in the case of SMMC-7721 cells were pretreated with excess anti-EGFRmonoclonal antibody C225(cetuximab) for 12h, the fluorescence intensity of DOX from GE11-DOX was obviously reduced. Both theconfocal microscopyand flow cytometry results indicated that GE11-DOX was taken up through EGFR-mediated endocytosis (Fig. 5,Fig. 6)."	.	.	.	.	.
REF00005	PDC_00154	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	3.66 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma of no special type	EGFR-overexpressing MCF-7 cell	.	"To further confirm the specific endocytosis of GE11-DOX through EGFR, a competition assay was conducted[16]. As shown inFig. 5, in the case of SMMC-7721 cells were pretreated with excess anti-EGFRmonoclonal antibody C225(cetuximab) for 12h, the fluorescence intensity of DOX from GE11-DOX was obviously reduced. Both theconfocal microscopyand flow cytometry results indicated that GE11-DOX was taken up through EGFR-mediated endocytosis (Fig. 5,Fig. 6)."	.	.	.	.	.
REF00005	PDC_00154	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	32.2&micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"To further confirm the specific endocytosis of GE11-DOX through EGFR, a competition assay was conducted[16]. As shown inFig. 5, in the case of SMMC-7721 cells were pretreated with excess anti-EGFRmonoclonal antibody C225(cetuximab) for 12h, the fluorescence intensity of DOX from GE11-DOX was obviously reduced. Both theconfocal microscopyand flow cytometry results indicated that GE11-DOX was taken up through EGFR-mediated endocytosis (Fig. 5,Fig. 6)."	.	.	.	.	.
REF00009	PDC_00325	Castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	97 &plusmn; 41 nM	nM	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	.	.	.	"Mice bearing established DU145 tumors were dosed with equimolar amounts of SAN1GSC, SAN1, sunitinib, and [d-Lys6]-GnRH for a period of 20 days. Tumor growth delay was evident in all mice treated with SAN1GSC (Fig. 5A and B), with an average tumor volume at day 20 of 689 &plusmn; 102 mm3significantly smaller in comparison with SAN1 (1,010 &plusmn; 114 mm3,P< 0.001) and sunitinib-treated mice (1197 &plusmn; 248,P< 0.001) or for mice treated with [d-Lys6]-GnRH (1248 &plusmn; 108 mm3,P< 0.001). On day 20, the average tumor weight for SAN1GSC-treated mice was 0.50 &plusmn; 0.11 g compared with 0.75 &plusmn; 0.33 g for SAN1, (P= 0.038 vs. SAN1GSC), 0.91 &plusmn; 0.27 g for sunitinib, (P= 0.003 vs. SAN1GSC), and 0.82 &plusmn; 0.22 g for [d-Lys6]-GnRH-treated mice (P= 0.003 vs. SAN1GSC). All treatments were well tolerated with no noticeable body weight loss or overt toxicity compared with the vehicle group (Supplementary Fig. S5). To investigate whether SAN1GSC dosing increased the drug payload to the tumor site, concentrations of SAN1, and of SAN1 derived from SAN1GSC administration, were determined in blood and tumors in samples obtained 1 hour postdose after day 20 of treatment (Fig. 5C). Measurements of SAN1 at the tumor tissue revealed approximately four times higher SAN1 in SAN1GSC-treated mice compared with SAN1-treated mice (113 &plusmn; 35 vs. 31 &plusmn; 8 nmol/L), with a tumor/blood ratio for SAN1 formed from SAN1GSC of 0.55 versus 0.16 for SAN1-treated mice."	.
REF00009	PDC_00325	Castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	91 &plusmn; 36 nM	nM	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	.	.	.	"Mice bearing established DU145 tumors were dosed with equimolar amounts of SAN1GSC, SAN1, sunitinib, and [d-Lys6]-GnRH for a period of 20 days. Tumor growth delay was evident in all mice treated with SAN1GSC (Fig. 5A and B), with an average tumor volume at day 20 of 689 &plusmn; 102 mm3significantly smaller in comparison with SAN1 (1,010 &plusmn; 114 mm3,P< 0.001) and sunitinib-treated mice (1197 &plusmn; 248,P< 0.001) or for mice treated with [d-Lys6]-GnRH (1248 &plusmn; 108 mm3,P< 0.001). On day 20, the average tumor weight for SAN1GSC-treated mice was 0.50 &plusmn; 0.11 g compared with 0.75 &plusmn; 0.33 g for SAN1, (P= 0.038 vs. SAN1GSC), 0.91 &plusmn; 0.27 g for sunitinib, (P= 0.003 vs. SAN1GSC), and 0.82 &plusmn; 0.22 g for [d-Lys6]-GnRH-treated mice (P= 0.003 vs. SAN1GSC). All treatments were well tolerated with no noticeable body weight loss or overt toxicity compared with the vehicle group (Supplementary Fig. S5). To investigate whether SAN1GSC dosing increased the drug payload to the tumor site, concentrations of SAN1, and of SAN1 derived from SAN1GSC administration, were determined in blood and tumors in samples obtained 1 hour postdose after day 20 of treatment (Fig. 5C). Measurements of SAN1 at the tumor tissue revealed approximately four times higher SAN1 in SAN1GSC-treated mice compared with SAN1-treated mice (113 &plusmn; 35 vs. 31 &plusmn; 8 nmol/L), with a tumor/blood ratio for SAN1 formed from SAN1GSC of 0.55 versus 0.16 for SAN1-treated mice."	.
REF00009	PDC_00325	Castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	74 &plusmn; 36 nM	nM	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	.	.	.	"Mice bearing established DU145 tumors were dosed with equimolar amounts of SAN1GSC, SAN1, sunitinib, and [d-Lys6]-GnRH for a period of 20 days. Tumor growth delay was evident in all mice treated with SAN1GSC (Fig. 5A and B), with an average tumor volume at day 20 of 689 &plusmn; 102 mm3significantly smaller in comparison with SAN1 (1,010 &plusmn; 114 mm3,P< 0.001) and sunitinib-treated mice (1197 &plusmn; 248,P< 0.001) or for mice treated with [d-Lys6]-GnRH (1248 &plusmn; 108 mm3,P< 0.001). On day 20, the average tumor weight for SAN1GSC-treated mice was 0.50 &plusmn; 0.11 g compared with 0.75 &plusmn; 0.33 g for SAN1, (P= 0.038 vs. SAN1GSC), 0.91 &plusmn; 0.27 g for sunitinib, (P= 0.003 vs. SAN1GSC), and 0.82 &plusmn; 0.22 g for [d-Lys6]-GnRH-treated mice (P= 0.003 vs. SAN1GSC). All treatments were well tolerated with no noticeable body weight loss or overt toxicity compared with the vehicle group (Supplementary Fig. S5). To investigate whether SAN1GSC dosing increased the drug payload to the tumor site, concentrations of SAN1, and of SAN1 derived from SAN1GSC administration, were determined in blood and tumors in samples obtained 1 hour postdose after day 20 of treatment (Fig. 5C). Measurements of SAN1 at the tumor tissue revealed approximately four times higher SAN1 in SAN1GSC-treated mice compared with SAN1-treated mice (113 &plusmn; 35 vs. 31 &plusmn; 8 nmol/L), with a tumor/blood ratio for SAN1 formed from SAN1GSC of 0.55 versus 0.16 for SAN1-treated mice."	.
REF00009	PDC_00325	Castration-resistant prostate cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	37 &plusmn; 6 nM	nM	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	.	.	.	"Mice bearing established DU145 tumors were dosed with equimolar amounts of SAN1GSC, SAN1, sunitinib, and [d-Lys6]-GnRH for a period of 20 days. Tumor growth delay was evident in all mice treated with SAN1GSC (Fig. 5A and B), with an average tumor volume at day 20 of 689 &plusmn; 102 mm3significantly smaller in comparison with SAN1 (1,010 &plusmn; 114 mm3,P< 0.001) and sunitinib-treated mice (1197 &plusmn; 248,P< 0.001) or for mice treated with [d-Lys6]-GnRH (1248 &plusmn; 108 mm3,P< 0.001). On day 20, the average tumor weight for SAN1GSC-treated mice was 0.50 &plusmn; 0.11 g compared with 0.75 &plusmn; 0.33 g for SAN1, (P= 0.038 vs. SAN1GSC), 0.91 &plusmn; 0.27 g for sunitinib, (P= 0.003 vs. SAN1GSC), and 0.82 &plusmn; 0.22 g for [d-Lys6]-GnRH-treated mice (P= 0.003 vs. SAN1GSC). All treatments were well tolerated with no noticeable body weight loss or overt toxicity compared with the vehicle group (Supplementary Fig. S5). To investigate whether SAN1GSC dosing increased the drug payload to the tumor site, concentrations of SAN1, and of SAN1 derived from SAN1GSC administration, were determined in blood and tumors in samples obtained 1 hour postdose after day 20 of treatment (Fig. 5C). Measurements of SAN1 at the tumor tissue revealed approximately four times higher SAN1 in SAN1GSC-treated mice compared with SAN1-treated mice (113 &plusmn; 35 vs. 31 &plusmn; 8 nmol/L), with a tumor/blood ratio for SAN1 formed from SAN1GSC of 0.55 versus 0.16 for SAN1-treated mice."	.
REF00009	PDC_00267	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	2.9 (8.5 &plusmn; 0.1) nM	nM	.	.	.	.	Normal	COS-7 cell	.	.	.	.	.	.	.
REF00009	PDC_00268	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	3.0 (8.5 &plusmn; 0.1) nM	nM	.	.	.	.	Normal	COS-7 cell	.	.	.	.	.	.	.
REF00009	PDC_00269	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	2.8 (8.5 &plusmn; 0.1) nM	nM	.	.	.	.	Normal	COS-7 cell	.	.	.	.	.	.	.
REF00009	PDC_00270	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	8.9 nM	nM	.	.	.	.	Normal	COS-7 cell	.	.	.	.	.	.	.
REF00009	PDC_00267	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	209 (6.7 &plusmn; 0.1) nM	nM	.	.	.	.	Normal	COS-7 cell	.	.	.	.	.	.	.
REF00009	PDC_00268	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Effective Concentration (EC50)	226 (6.6 &plusmn; 0.1) nM	nM	.	.	.	.	Normal	COS-7 cell	.	.	.	.	.	.	.
REF00009	PDC_00267	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	18 (4.8 &plusmn; 0.1) &mu;M	&mu;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	.	.	.	.	.
REF00009	PDC_00268	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	3.6 (5.4 &plusmn; 0.1) &mu;M	&mu;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	.	.	.	.	.
REF00009	PDC_00269	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	4.0 (5.4 &plusmn; 0.1) &mu;M	&mu;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	.	.	.	.	.
REF00009	PDC_00270	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	2.0 (5.7 &plusmn; 0.1) &mu;M	&mu;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	.	.	.	.	.	.	.
REF00009	PDC_00267	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	25 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	T-47D cell	.	.	.	.	.	.	.
REF00009	PDC_00268	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	7.7 (5.1 &plusmn; 0.1) &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	T-47D cell	.	.	.	.	.	.	.
REF00009	PDC_00269	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	10 &micro;M	&micro;M	.	.	.	.	Invasive breast carcinoma	T-47D cell	.	.	.	.	.	.	.
REF00009	PDC_00270	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	5.0 (5.3 &plusmn; 0.1) &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	T-47D cell	.	.	.	.	.	.	.
REF00009	PDC_00267	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	25 &micro;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	.	.
REF00009	PDC_00268	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	8.1 (5.1 &plusmn; 0.1) &mu;M	&mu;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	.	.
REF00009	PDC_00269	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	3.8 (5.4 &plusmn; 0.1) &mu;M	&micro;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	.	.
REF00009	PDC_00270	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half Maximal Inhibitory Concentration (IC50)	4.2 (5.4 &plusmn; 0.1) &mu;M	&mu;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	.	.
REF00320	PDC_00363	Arthritis	DBA/1 male mice with arthritis.	Obtained from the Model Organism Data	.	Reduction of arthritis severity	7.87	.	.	.	.	.	.	.	.	.	31 days	250 &mu;g/0.1mL	Assessment of arthritis	"The main characteristic of RA is joint deformation due to severe inflammation, therefore we followed the TPC effect on arthritis score in CIA mice. CIA mice were subjected to TPC, orally or s.c., and compared to mice treated with PBS. As detailed in Fig. Fig.1a,b,1a,b, we observed a significantly lower arthritis score in TPCtreated mice compared with PBStreated mice (P < 0.05). Arthritis score was lower in both the TPC orally and TPC s.c.treated groups starting at 2 weeks after disease induction (day 14, 20 days after treatment initiation), until the mice were sacrificed (day 31). When the mice were sacrificed, both the TPCtreated groups had a mean arthritis score of 1.5 (range from 0 to 4), while both the PBStreated groups had a mean arthritis score of 11.8 (range from 10 to 14) (P < 0.001). TPC orally treated mice had a mean arthritis score of 1.6 1.5, while PBS orally treated mice had a mean arthritis score of 12.6 1.14 (P < 0.001). Moreover, TPC s.c.treated mice had a mean arthritis score of 1.4 0.84, whereas PBS s.c.treated mice had a mean arthritis score of 11 1.22 (P < 0.001). Representative pictures of mice joints shown in Fig. Fig.1c1c demonstrate a significant difference in inflammation in the TPCtreated mice in comparison with the PBStreated ones. PBStreated mice developed oedema and erythema from the ankle to the entire leg, while TPCtreated mice exhibited milder symptoms."	"Dazdotuftide is a novel, small synthetic molecule. It is a peptide conjugate comprised of tuftsin and phosphorylcholine that are covalently attached. The phosphorylcholine (PPC) moiety is based on a sequence from helminths secretory molecules which has been shown to be responsible for their immunoregulatory functions. Tuftsin is a naturally occurring endogenous immunomodulatory tetra-peptide (Thr-Lys-Pro-Arg) produced in the spleen by enzymatic cleavage of the Fc-domain of the heavy chain of IgG. The peptide is coupled to diazotized 4-aminophenyphosphorylchloride to form an azo bond between the tuftsin and PC. Extensive research has been done on Tuftsin and PPC separately, and the activities of each of them towards immune regulation. Dazdotuftide has been suggested to provide a strong synergistic effect, far surpassing the efficacy of the compounds given separately."
REF00327	PDC_00360	Solid tumor	.	Identified from the Human Clinical Data	.	Grade 3 increased GGT	8.30%	%	.	.	.	24 patients with various types of solid tumors.	.	.	.	.	.	9.6 mg/m<sup>2</sup> BIW	.	"24 patients were enrolled with various types of solid tumors across both dose escalation cohorts (see table). BIW RP2D was determined as 7.2 mg/m<sup>2</sup>. The 2 patients with DLTs at 9.6 mg/m<sup>2</sup> BIW experienced grade 3 increased GGT or fatigue. QW dose escalation continues at 20 mg/m<sup>2</sup>. Mean number of cycles received = 2.3 months (N = 24), with no objective responses observed to date in this unselected population."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00327	PDC_00360	Solid tumor	.	Identified from the Human Clinical Data	.	Fatigue	8.30%	%	.	.	.	24 patients with various types of solid tumors.	.	.	.	.	.	9.6 mg/m<sup>2</sup> BIW	.	"24 patients were enrolled with various types of solid tumors across both dose escalation cohorts (see table). BIW RP2D was determined as 7.2 mg/m<sup>2</sup>. The 2 patients with DLTs at 9.6 mg/m<sup>2</sup> BIW experienced grade 3 increased GGT or fatigue. QW dose escalation continues at 20 mg/m<sup>2</sup>. Mean number of cycles received = 2.3 months (N = 24), with no objective responses observed to date in this unselected population."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00327	PDC_00360	Lung squamous cell carcinoma	Cell-derived xenograftmodel inmiceimplanted with MT1-positive EBC-1 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	100%	%	.	.	.	.	Lung squamous cell carcinoma	EBC-1 cell	.	.	14 days	10mg/kg	.	"Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00327	PDC_00360	Fibrosarcoma	Cell-derived xenograftmodel inmiceimplanted with MT1-positive HT-1080 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	100%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	14 days	10 mg/kg biw	.	"Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00327	PDC_00360	Fibrosarcoma	Cell-derived xenograftmodel inmiceimplanted with MT1-positive HT-1080 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	100%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	14 days	3 mg/kg biw	.	"Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00327	PDC_00360	Fibrosarcoma	Cell-derived xenograftmodel inmiceimplanted with MT1-positive HT-1080 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	27%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	14 days	1 mg/kg biw	.	"Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00327	PDC_00360	Fibrosarcoma	Cell-derived xenograftmodel inmiceimplanted with MT1-positive HT-1080 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	100%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	14 days	10 mg/kg qw	.	"Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00327	PDC_00360	Fibrosarcoma	Cell-derived xenograftmodel inmiceimplanted with MT1-positive HT-1080 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	88%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	14 days	3 mg/kg qw	.	"Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00327	PDC_00360	Fibrosarcoma	Cell-derived xenograftmodel inmiceimplanted with MT1-positive HT-1080 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	18%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	14 days	1 mg/kg qw	.	"Treatment with BDCs containing the most labile linkers (BT17BDC17 or BT1718) showed rapid and complete tumour clearance (EBC-1 cells), while BDCs containing more stabilised linkers showed comparatively reduced efficacy (fig. 5) suggesting that target internalisation is not the sole mechanism of action for BDC efficacy and that extracellular cleavage and release of toxin within the local tumour environment likely also contribute. Only the most labile BDC (BT17BDC17) caused any significant toxicity (17% 9.7 body weight loss); all others were well tolerated (<10% body weight loss at 10 mg/kg tiw). Optimal therapeutic index was achieved with BT1718. Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10 mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00324	PDC_00364	Colon adenocarcinoma	Female Swiss nude mice HT-29 CRC cells xenograft models.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	29.40%	%	.	.	.	.	Colon cancer	HT29 cell	.	.	23 days	"33 MBq, single dose"	.	"The antitumor effects of [177Lu]Lu-DPI-4452 were assessed in HT-29 and SK-RC-52 xenografts. Tumor-bearing mice were randomized into 4 groups and injected with single doses of vehicle, 100 or 33 MBq of [177Lu]Lu-DPI-4452, or 3 once-weekly 33-MBq doses of [177Lu]Lu-DPI-4452. Treatment was well tolerated, including no significant changes in kidney function biomarkers (Supplemental Figs. 911). All treatment groups, except HT-29 xenograft-bearing mice receiving a single dose of 33 MBq, had significantly reduced tumor volumes compared with vehicle controls by day 16 (HT-29) or day 13 (SK-RC-52). Both 100-MBq and 3 once-weekly 33-MBq doses produced maximal tumor growth inhibition at day 23 for HT-29 xenografts and day 36 for SK-RC-52 xenografts, although 3 once-weekly 33-MBq doses produced a more sustained effect than a single 100-MBq dose in both models. No significant difference in tumor size for SK-RC-52 xenografts was observed at day 36 after treatment with single 100- or 33-MBq doses of [177Lu]Lu-DPI-4452 (Supplemental Table 4). These findings were consistent with the improved survival seen in treated mice compared with control mice (Supplemental Fig. 14; Supplemental Table 5). SPECT/CT analysis of 3 mice with xenografts per treatment arm revealed high tumor uptake in both models that was not modulated by repeated [177Lu]Lu-DPI-4452 treatments. Similar radioactivity was found in SK-RC-52 tumors for all doses, suggesting that uptake was already maximal at the lowest dose of 33 MBq. These findings demonstrated a strong antitumor effect of [177Lu]Lu-DPI-4452 on CAIX-expressing tumors and suggested dose fractionation may be beneficial."	"Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to bicarbonate ions and protons. Of the 12 catalytically active CAs in humans, 4 are located on the extracellular surface. Two of these, CAIX and CAXII, are highly expressed in tumors and contribute to maintenance of the acidic tumor microenvironment. Many healthy tissues express CAXII, whereas normal CAIX expression is restricted to the gastrointestinal epithelia. In clear cell renal cell carcinomas (ccRCC), impaired von Hippel-Lindau tumor suppressor function causes deregulation of hypoxia-inducible factor 1&alpha; expression, resulting in constitutive CAIX expression. Transcriptional regulation by hypoxia-inducible factor 1&alpha; leads to CAIX overexpression in hypoxic conditions and aberrant expression in some solid tumors, including colorectal cancer (CRC), breast cancer, and pancreatic ductal adenocarcinoma (PDAC). CAIX overexpression is associated with tumor progression, poor prognosis, and metastasis development. With restricted expression in healthy tissues and near ubiquitous cell surface expression in ccRCC and hypoxic tumors (7), CAIX represents a promising diagnostic and therapeutic target. DPI-4452 is a CAIX-targeting peptidomimetic carrying a DOTA cage, allowing chelation with radionuclides such as 68Ga ([68Ga]Ga) or 177Lu ([177Lu]Lu) for theranostic purposes. Here, we report on the tumor-specific expression of CAIX and preclinical characterization of DPI-4452 in proof-of-concept studies, including safety, biodistribution, pharmacokinetics, and antitumor efficacy."
REF00324	PDC_00364	Colon adenocarcinoma	Female Swiss nude mice HT-29 CRC cells xenograft models.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	82.40%	%	.	.	.	.	Colon cancer	HT29 cell	.	.	23 days	"100 MBq, single dose"	.	"The antitumor effects of [177Lu]Lu-DPI-4452 were assessed in HT-29 and SK-RC-52 xenografts. Tumor-bearing mice were randomized into 4 groups and injected with single doses of vehicle, 100 or 33 MBq of [177Lu]Lu-DPI-4452, or 3 once-weekly 33-MBq doses of [177Lu]Lu-DPI-4452. Treatment was well tolerated, including no significant changes in kidney function biomarkers (Supplemental Figs. 911). All treatment groups, except HT-29 xenograft-bearing mice receiving a single dose of 33 MBq, had significantly reduced tumor volumes compared with vehicle controls by day 16 (HT-29) or day 13 (SK-RC-52). Both 100-MBq and 3 once-weekly 33-MBq doses produced maximal tumor growth inhibition at day 23 for HT-29 xenografts and day 36 for SK-RC-52 xenografts, although 3 once-weekly 33-MBq doses produced a more sustained effect than a single 100-MBq dose in both models. No significant difference in tumor size for SK-RC-52 xenografts was observed at day 36 after treatment with single 100- or 33-MBq doses of [177Lu]Lu-DPI-4452 (Supplemental Table 4). These findings were consistent with the improved survival seen in treated mice compared with control mice (Supplemental Fig. 14; Supplemental Table 5). SPECT/CT analysis of 3 mice with xenografts per treatment arm revealed high tumor uptake in both models that was not modulated by repeated [177Lu]Lu-DPI-4452 treatments. Similar radioactivity was found in SK-RC-52 tumors for all doses, suggesting that uptake was already maximal at the lowest dose of 33 MBq. These findings demonstrated a strong antitumor effect of [177Lu]Lu-DPI-4452 on CAIX-expressing tumors and suggested dose fractionation may be beneficial."	"Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to bicarbonate ions and protons. Of the 12 catalytically active CAs in humans, 4 are located on the extracellular surface. Two of these, CAIX and CAXII, are highly expressed in tumors and contribute to maintenance of the acidic tumor microenvironment. Many healthy tissues express CAXII, whereas normal CAIX expression is restricted to the gastrointestinal epithelia. In clear cell renal cell carcinomas (ccRCC), impaired von Hippel-Lindau tumor suppressor function causes deregulation of hypoxia-inducible factor 1&alpha; expression, resulting in constitutive CAIX expression. Transcriptional regulation by hypoxia-inducible factor 1&alpha; leads to CAIX overexpression in hypoxic conditions and aberrant expression in some solid tumors, including colorectal cancer (CRC), breast cancer, and pancreatic ductal adenocarcinoma (PDAC). CAIX overexpression is associated with tumor progression, poor prognosis, and metastasis development. With restricted expression in healthy tissues and near ubiquitous cell surface expression in ccRCC and hypoxic tumors (7), CAIX represents a promising diagnostic and therapeutic target. DPI-4452 is a CAIX-targeting peptidomimetic carrying a DOTA cage, allowing chelation with radionuclides such as 68Ga ([68Ga]Ga) or 177Lu ([177Lu]Lu) for theranostic purposes. Here, we report on the tumor-specific expression of CAIX and preclinical characterization of DPI-4452 in proof-of-concept studies, including safety, biodistribution, pharmacokinetics, and antitumor efficacy."
REF00324	PDC_00364	Colon adenocarcinoma	Female Swiss nude mice HT-29 CRC cells xenograft models.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	82.40%	%	.	.	.	.	Colon cancer	HT29 cell	.	.	23 days	"33 MBq, QW3"	.	"The antitumor effects of [177Lu]Lu-DPI-4452 were assessed in HT-29 and SK-RC-52 xenografts. Tumor-bearing mice were randomized into 4 groups and injected with single doses of vehicle, 100 or 33 MBq of [177Lu]Lu-DPI-4452, or 3 once-weekly 33-MBq doses of [177Lu]Lu-DPI-4452. Treatment was well tolerated, including no significant changes in kidney function biomarkers (Supplemental Figs. 911). All treatment groups, except HT-29 xenograft-bearing mice receiving a single dose of 33 MBq, had significantly reduced tumor volumes compared with vehicle controls by day 16 (HT-29) or day 13 (SK-RC-52). Both 100-MBq and 3 once-weekly 33-MBq doses produced maximal tumor growth inhibition at day 23 for HT-29 xenografts and day 36 for SK-RC-52 xenografts, although 3 once-weekly 33-MBq doses produced a more sustained effect than a single 100-MBq dose in both models. No significant difference in tumor size for SK-RC-52 xenografts was observed at day 36 after treatment with single 100- or 33-MBq doses of [177Lu]Lu-DPI-4452 (Supplemental Table 4). These findings were consistent with the improved survival seen in treated mice compared with control mice (Supplemental Fig. 14; Supplemental Table 5). SPECT/CT analysis of 3 mice with xenografts per treatment arm revealed high tumor uptake in both models that was not modulated by repeated [177Lu]Lu-DPI-4452 treatments. Similar radioactivity was found in SK-RC-52 tumors for all doses, suggesting that uptake was already maximal at the lowest dose of 33 MBq. These findings demonstrated a strong antitumor effect of [177Lu]Lu-DPI-4452 on CAIX-expressing tumors and suggested dose fractionation may be beneficial."	"Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to bicarbonate ions and protons. Of the 12 catalytically active CAs in humans, 4 are located on the extracellular surface. Two of these, CAIX and CAXII, are highly expressed in tumors and contribute to maintenance of the acidic tumor microenvironment. Many healthy tissues express CAXII, whereas normal CAIX expression is restricted to the gastrointestinal epithelia. In clear cell renal cell carcinomas (ccRCC), impaired von Hippel-Lindau tumor suppressor function causes deregulation of hypoxia-inducible factor 1&alpha; expression, resulting in constitutive CAIX expression. Transcriptional regulation by hypoxia-inducible factor 1&alpha; leads to CAIX overexpression in hypoxic conditions and aberrant expression in some solid tumors, including colorectal cancer (CRC), breast cancer, and pancreatic ductal adenocarcinoma (PDAC). CAIX overexpression is associated with tumor progression, poor prognosis, and metastasis development. With restricted expression in healthy tissues and near ubiquitous cell surface expression in ccRCC and hypoxic tumors (7), CAIX represents a promising diagnostic and therapeutic target. DPI-4452 is a CAIX-targeting peptidomimetic carrying a DOTA cage, allowing chelation with radionuclides such as 68Ga ([68Ga]Ga) or 177Lu ([177Lu]Lu) for theranostic purposes. Here, we report on the tumor-specific expression of CAIX and preclinical characterization of DPI-4452 in proof-of-concept studies, including safety, biodistribution, pharmacokinetics, and antitumor efficacy."
REF00324	PDC_00364	Renal cancer	Female Swiss nude mice SK-RC-52 ccRCC cells xenograft models.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	77.80%	%	.	.	.	.	Renal cell carcinoma	SK-RC-52 cell	.	.	15 days	"33 MBq, single dose"	.	"The antitumor effects of [177Lu]Lu-DPI-4452 were assessed in HT-29 and SK-RC-52 xenografts. Tumor-bearing mice were randomized into 4 groups and injected with single doses of vehicle, 100 or 33 MBq of [177Lu]Lu-DPI-4452, or 3 once-weekly 33-MBq doses of [177Lu]Lu-DPI-4452. Treatment was well tolerated, including no significant changes in kidney function biomarkers (Supplemental Figs. 911). All treatment groups, except HT-29 xenograft-bearing mice receiving a single dose of 33 MBq, had significantly reduced tumor volumes compared with vehicle controls by day 16 (HT-29) or day 13 (SK-RC-52). Both 100-MBq and 3 once-weekly 33-MBq doses produced maximal tumor growth inhibition at day 23 for HT-29 xenografts and day 36 for SK-RC-52 xenografts, although 3 once-weekly 33-MBq doses produced a more sustained effect than a single 100-MBq dose in both models. No significant difference in tumor size for SK-RC-52 xenografts was observed at day 36 after treatment with single 100- or 33-MBq doses of [177Lu]Lu-DPI-4452 (Supplemental Table 4). These findings were consistent with the improved survival seen in treated mice compared with control mice (Supplemental Fig. 14; Supplemental Table 5). SPECT/CT analysis of 3 mice with xenografts per treatment arm revealed high tumor uptake in both models that was not modulated by repeated [177Lu]Lu-DPI-4452 treatments. Similar radioactivity was found in SK-RC-52 tumors for all doses, suggesting that uptake was already maximal at the lowest dose of 33 MBq. These findings demonstrated a strong antitumor effect of [177Lu]Lu-DPI-4452 on CAIX-expressing tumors and suggested dose fractionation may be beneficial."	"Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to bicarbonate ions and protons. Of the 12 catalytically active CAs in humans, 4 are located on the extracellular surface. Two of these, CAIX and CAXII, are highly expressed in tumors and contribute to maintenance of the acidic tumor microenvironment. Many healthy tissues express CAXII, whereas normal CAIX expression is restricted to the gastrointestinal epithelia. In clear cell renal cell carcinomas (ccRCC), impaired von Hippel-Lindau tumor suppressor function causes deregulation of hypoxia-inducible factor 1&alpha; expression, resulting in constitutive CAIX expression. Transcriptional regulation by hypoxia-inducible factor 1&alpha; leads to CAIX overexpression in hypoxic conditions and aberrant expression in some solid tumors, including colorectal cancer (CRC), breast cancer, and pancreatic ductal adenocarcinoma (PDAC). CAIX overexpression is associated with tumor progression, poor prognosis, and metastasis development. With restricted expression in healthy tissues and near ubiquitous cell surface expression in ccRCC and hypoxic tumors (7), CAIX represents a promising diagnostic and therapeutic target. DPI-4452 is a CAIX-targeting peptidomimetic carrying a DOTA cage, allowing chelation with radionuclides such as 68Ga ([68Ga]Ga) or 177Lu ([177Lu]Lu) for theranostic purposes. Here, we report on the tumor-specific expression of CAIX and preclinical characterization of DPI-4452 in proof-of-concept studies, including safety, biodistribution, pharmacokinetics, and antitumor efficacy."
REF00324	PDC_00364	Renal cancer	Female Swiss nude mice SK-RC-52 ccRCC cells xenograft models.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	73.30%	%	.	.	.	.	Renal cell carcinoma	SK-RC-52 cell	.	.	15 days	"100 MBq, single dose"	.	"The antitumor effects of [177Lu]Lu-DPI-4452 were assessed in HT-29 and SK-RC-52 xenografts. Tumor-bearing mice were randomized into 4 groups and injected with single doses of vehicle, 100 or 33 MBq of [177Lu]Lu-DPI-4452, or 3 once-weekly 33-MBq doses of [177Lu]Lu-DPI-4452. Treatment was well tolerated, including no significant changes in kidney function biomarkers (Supplemental Figs. 911). All treatment groups, except HT-29 xenograft-bearing mice receiving a single dose of 33 MBq, had significantly reduced tumor volumes compared with vehicle controls by day 16 (HT-29) or day 13 (SK-RC-52). Both 100-MBq and 3 once-weekly 33-MBq doses produced maximal tumor growth inhibition at day 23 for HT-29 xenografts and day 36 for SK-RC-52 xenografts, although 3 once-weekly 33-MBq doses produced a more sustained effect than a single 100-MBq dose in both models. No significant difference in tumor size for SK-RC-52 xenografts was observed at day 36 after treatment with single 100- or 33-MBq doses of [177Lu]Lu-DPI-4452 (Supplemental Table 4). These findings were consistent with the improved survival seen in treated mice compared with control mice (Supplemental Fig. 14; Supplemental Table 5). SPECT/CT analysis of 3 mice with xenografts per treatment arm revealed high tumor uptake in both models that was not modulated by repeated [177Lu]Lu-DPI-4452 treatments. Similar radioactivity was found in SK-RC-52 tumors for all doses, suggesting that uptake was already maximal at the lowest dose of 33 MBq. These findings demonstrated a strong antitumor effect of [177Lu]Lu-DPI-4452 on CAIX-expressing tumors and suggested dose fractionation may be beneficial."	"Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to bicarbonate ions and protons. Of the 12 catalytically active CAs in humans, 4 are located on the extracellular surface. Two of these, CAIX and CAXII, are highly expressed in tumors and contribute to maintenance of the acidic tumor microenvironment. Many healthy tissues express CAXII, whereas normal CAIX expression is restricted to the gastrointestinal epithelia. In clear cell renal cell carcinomas (ccRCC), impaired von Hippel-Lindau tumor suppressor function causes deregulation of hypoxia-inducible factor 1&alpha; expression, resulting in constitutive CAIX expression. Transcriptional regulation by hypoxia-inducible factor 1&alpha; leads to CAIX overexpression in hypoxic conditions and aberrant expression in some solid tumors, including colorectal cancer (CRC), breast cancer, and pancreatic ductal adenocarcinoma (PDAC). CAIX overexpression is associated with tumor progression, poor prognosis, and metastasis development. With restricted expression in healthy tissues and near ubiquitous cell surface expression in ccRCC and hypoxic tumors (7), CAIX represents a promising diagnostic and therapeutic target. DPI-4452 is a CAIX-targeting peptidomimetic carrying a DOTA cage, allowing chelation with radionuclides such as 68Ga ([68Ga]Ga) or 177Lu ([177Lu]Lu) for theranostic purposes. Here, we report on the tumor-specific expression of CAIX and preclinical characterization of DPI-4452 in proof-of-concept studies, including safety, biodistribution, pharmacokinetics, and antitumor efficacy."
REF00324	PDC_00364	Renal cancer	Female Swiss nude mice SK-RC-52 ccRCC cells xenograft models.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	84.40%	%	.	.	.	.	Renal cell carcinoma	SK-RC-52 cell	.	.	15 days	"33 MBq, QW3"	.	"The antitumor effects of [177Lu]Lu-DPI-4452 were assessed in HT-29 and SK-RC-52 xenografts. Tumor-bearing mice were randomized into 4 groups and injected with single doses of vehicle, 100 or 33 MBq of [177Lu]Lu-DPI-4452, or 3 once-weekly 33-MBq doses of [177Lu]Lu-DPI-4452. Treatment was well tolerated, including no significant changes in kidney function biomarkers (Supplemental Figs. 911). All treatment groups, except HT-29 xenograft-bearing mice receiving a single dose of 33 MBq, had significantly reduced tumor volumes compared with vehicle controls by day 16 (HT-29) or day 13 (SK-RC-52). Both 100-MBq and 3 once-weekly 33-MBq doses produced maximal tumor growth inhibition at day 23 for HT-29 xenografts and day 36 for SK-RC-52 xenografts, although 3 once-weekly 33-MBq doses produced a more sustained effect than a single 100-MBq dose in both models. No significant difference in tumor size for SK-RC-52 xenografts was observed at day 36 after treatment with single 100- or 33-MBq doses of [177Lu]Lu-DPI-4452 (Supplemental Table 4). These findings were consistent with the improved survival seen in treated mice compared with control mice (Supplemental Fig. 14; Supplemental Table 5). SPECT/CT analysis of 3 mice with xenografts per treatment arm revealed high tumor uptake in both models that was not modulated by repeated [177Lu]Lu-DPI-4452 treatments. Similar radioactivity was found in SK-RC-52 tumors for all doses, suggesting that uptake was already maximal at the lowest dose of 33 MBq. These findings demonstrated a strong antitumor effect of [177Lu]Lu-DPI-4452 on CAIX-expressing tumors and suggested dose fractionation may be beneficial."	"Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to bicarbonate ions and protons. Of the 12 catalytically active CAs in humans, 4 are located on the extracellular surface. Two of these, CAIX and CAXII, are highly expressed in tumors and contribute to maintenance of the acidic tumor microenvironment. Many healthy tissues express CAXII, whereas normal CAIX expression is restricted to the gastrointestinal epithelia. In clear cell renal cell carcinomas (ccRCC), impaired von Hippel-Lindau tumor suppressor function causes deregulation of hypoxia-inducible factor 1&alpha; expression, resulting in constitutive CAIX expression. Transcriptional regulation by hypoxia-inducible factor 1&alpha; leads to CAIX overexpression in hypoxic conditions and aberrant expression in some solid tumors, including colorectal cancer (CRC), breast cancer, and pancreatic ductal adenocarcinoma (PDAC). CAIX overexpression is associated with tumor progression, poor prognosis, and metastasis development. With restricted expression in healthy tissues and near ubiquitous cell surface expression in ccRCC and hypoxic tumors (7), CAIX represents a promising diagnostic and therapeutic target. DPI-4452 is a CAIX-targeting peptidomimetic carrying a DOTA cage, allowing chelation with radionuclides such as 68Ga ([68Ga]Ga) or 177Lu ([177Lu]Lu) for theranostic purposes. Here, we report on the tumor-specific expression of CAIX and preclinical characterization of DPI-4452 in proof-of-concept studies, including safety, biodistribution, pharmacokinetics, and antitumor efficacy."
REF00323	PDC_00365	Clear cell renal cell carcinoma	.	Identified from the Human Clinical Data	High Expreesion	SUV max values	109	.	.	.	.	48 years old patient with metastatic ccRCC.	.	.	.	.	.	185 MBq (&plusmn;20%)	.	"After [68Ga]Ga-DPI-4452 administration, high tumor-specific uptake was observed as early as 15min and was sustained for all time points assessed. One hour was chosen as the optimal time point on the basis of central reader visual assessment of image quality, visualization of all lesions, and heterogeneity in tumor uptake. Among all lesions, 17 metastases in bone, lymph nodes, lungs, pancreas, and parotid glands were not readily identifiable by conventional imaging. Low renal parenchymal uptake enabled identification of renal tumors. SUVmax 1h after administration across 36 lesions ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). In patients 1, 2, and 3, the highest SUVmax was 109, 106, and 212, respectively, whereas the highest SUVmean was 39, 62, and 89, respectively."	"Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC."
REF00323	PDC_00365	Clear cell renal cell carcinoma	.	Identified from the Human Clinical Data	High Expreesion	SUV max values	106	.	.	.	.	51 years old patient with metastatic ccRCC.	.	.	.	.	.	185 MBq (&plusmn;20%)	.	"After [68Ga]Ga-DPI-4452 administration, high tumor-specific uptake was observed as early as 15min and was sustained for all time points assessed. One hour was chosen as the optimal time point on the basis of central reader visual assessment of image quality, visualization of all lesions, and heterogeneity in tumor uptake. Among all lesions, 17 metastases in bone, lymph nodes, lungs, pancreas, and parotid glands were not readily identifiable by conventional imaging. Low renal parenchymal uptake enabled identification of renal tumors. SUVmax 1h after administration across 36 lesions ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). In patients 1, 2, and 3, the highest SUVmax was 109, 106, and 212, respectively, whereas the highest SUVmean was 39, 62, and 89, respectively."	"Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC."
REF00323	PDC_00365	Clear cell renal cell carcinoma	.	Identified from the Human Clinical Data	High Expreesion	SUV max values	212	.	.	.	.	54 years old patient with metastatic ccRCC.	.	.	.	.	.	185 MBq (&plusmn;20%)	.	"After [68Ga]Ga-DPI-4452 administration, high tumor-specific uptake was observed as early as 15min and was sustained for all time points assessed. One hour was chosen as the optimal time point on the basis of central reader visual assessment of image quality, visualization of all lesions, and heterogeneity in tumor uptake. Among all lesions, 17 metastases in bone, lymph nodes, lungs, pancreas, and parotid glands were not readily identifiable by conventional imaging. Low renal parenchymal uptake enabled identification of renal tumors. SUVmax 1h after administration across 36 lesions ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). In patients 1, 2, and 3, the highest SUVmax was 109, 106, and 212, respectively, whereas the highest SUVmean was 39, 62, and 89, respectively."	"Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC."
REF00323	PDC_00365	Clear cell renal cell carcinoma	.	Identified from the Human Clinical Data	High Expreesion	SUV mean values	39	.	.	.	.	48 years old patient with metastatic ccRCC.	.	.	.	.	.	185 MBq (&plusmn;20%)	.	"After [68Ga]Ga-DPI-4452 administration, high tumor-specific uptake was observed as early as 15min and was sustained for all time points assessed. One hour was chosen as the optimal time point on the basis of central reader visual assessment of image quality, visualization of all lesions, and heterogeneity in tumor uptake. Among all lesions, 17 metastases in bone, lymph nodes, lungs, pancreas, and parotid glands were not readily identifiable by conventional imaging. Low renal parenchymal uptake enabled identification of renal tumors. SUVmax 1h after administration across 36 lesions ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). In patients 1, 2, and 3, the highest SUVmax was 109, 106, and 212, respectively, whereas the highest SUVmean was 39, 62, and 89, respectively."	"Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC."
REF00323	PDC_00365	Clear cell renal cell carcinoma	.	Identified from the Human Clinical Data	High Expreesion	SUV mean values	62	.	.	.	.	51 years old patient with metastatic ccRCC.	.	.	.	.	.	185 MBq (&plusmn;20%)	.	"After [68Ga]Ga-DPI-4452 administration, high tumor-specific uptake was observed as early as 15min and was sustained for all time points assessed. One hour was chosen as the optimal time point on the basis of central reader visual assessment of image quality, visualization of all lesions, and heterogeneity in tumor uptake. Among all lesions, 17 metastases in bone, lymph nodes, lungs, pancreas, and parotid glands were not readily identifiable by conventional imaging. Low renal parenchymal uptake enabled identification of renal tumors. SUVmax 1h after administration across 36 lesions ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). In patients 1, 2, and 3, the highest SUVmax was 109, 106, and 212, respectively, whereas the highest SUVmean was 39, 62, and 89, respectively."	"Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC."
REF00323	PDC_00365	Clear cell renal cell carcinoma	.	Identified from the Human Clinical Data	High Expreesion	SUV mean values	89	.	.	.	.	54 years old patient with metastatic ccRCC.	.	.	.	.	.	185 MBq (&plusmn;20%)	.	"After [68Ga]Ga-DPI-4452 administration, high tumor-specific uptake was observed as early as 15min and was sustained for all time points assessed. One hour was chosen as the optimal time point on the basis of central reader visual assessment of image quality, visualization of all lesions, and heterogeneity in tumor uptake. Among all lesions, 17 metastases in bone, lymph nodes, lungs, pancreas, and parotid glands were not readily identifiable by conventional imaging. Low renal parenchymal uptake enabled identification of renal tumors. SUVmax 1h after administration across 36 lesions ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). In patients 1, 2, and 3, the highest SUVmax was 109, 106, and 212, respectively, whereas the highest SUVmean was 39, 62, and 89, respectively."	"Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC."
REF00323	PDC_00365	Clear cell renal cell carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Blood creatine kinase increase	33.30%	%	.	.	.	3 patients with metastatic ccRCC.	.	.	.	.	.	185 MBq (&plusmn;20%)	.	"No clinically significant toxicity was observed; treatment-emergent adverse events (headache and increased blood creatine kinase [1 each; 33.3%]) were not causally related to [68Ga]Ga-DPI-4452. No significant changes in vital signs, laboratory assessments, or electrocardiograms were observed."	"Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC."
REF00323	PDC_00365	Clear cell renal cell carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Headache	33.30%	%	.	.	.	3 patients with metastatic ccRCC.	.	.	.	.	.	185 MBq (&plusmn;20%)	.	"No clinically significant toxicity was observed; treatment-emergent adverse events (headache and increased blood creatine kinase [1 each; 33.3%]) were not causally related to [68Ga]Ga-DPI-4452. No significant changes in vital signs, laboratory assessments, or electrocardiograms were observed."	"Carbonic anhydrase IX (CAIX) is a cell-surface glycoprotein involved in acidbase regulation. Aberrant tumor expression contributes to extracellular acidification, promoting tumor progression. The CAIX-encoding gene is overexpressed in more than 90% of ccRCC cases, often because of alterations in the von HippelLindau gene. With physiologic CAIX expression restricted to gastrointestinal epithelia, high tumoral expression presents diagnostic and therapeutic opportunities. Indeed, PET/CT-based tumor visualization with 89Zr-labeled anti-CAIX antibodies ([89Zr]Zr-girentuximab) can aid diagnosis of localized and metastatic ccRCC and enable differentiation of indolent versus benign tumors, which is challenging with conventional imaging. The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic (68Ga) or therapeutic (177Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors. Here, we report the characteristics of diagnostic [68Ga]Ga-DPI-4452 in patients with ccRCC."
REF00326	PDC_00366	Ovarian cancer	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	48.30%	%	.	.	.	29 platinum-resistant ovarian cancer patients.	.	.	.	.	.	0.15 mg/kg	.	"Promising efficacy was observed in HGSOC patients (pts) who received prior 1-2L of TIT (if prior 2L, &ge;12m of time interval between 2L; and &ge;3m of time interval from the last TIT to CBP-1008 first dose). The ORR is 48.3%(14/29) and DCR is 82.8%(24/29), regardless of FR expression."	Folate receptor &alpha; (FR&alpha;) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class (FIC) bi-specific ligand drug conjugate targeting FR&alpha; and TRPV6 carrying monomethyl auristatin E (MMAE) as payload.
REF00326	PDC_00366	Ovarian cancer	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD) 	34.50%	%	.	.	.	29 platinum-resistant ovarian cancer patients.	.	.	.	.	.	0.15 mg/kg	.	"Promising efficacy was observed in HGSOC patients (pts) who received prior 1-2L of TIT (if prior 2L, &ge;12m of time interval between 2L; and &ge;3m of time interval from the last TIT to CBP-1008 first dose). The ORR is 48.3%(14/29) and DCR is 82.8%(24/29), regardless of FR expression."	Folate receptor &alpha; (FR&alpha;) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class (FIC) bi-specific ligand drug conjugate targeting FR&alpha; and TRPV6 carrying monomethyl auristatin E (MMAE) as payload.
REF00326	PDC_00366	Ovarian cancer	.	Identified from the Human Clinical Data	High Expreesion	Progressive disease (PD)	17.20%	%	.	.	.	29 platinum-resistant ovarian cancer patients.	.	.	.	.	.	0.15 mg/kg	.	"Promising efficacy was observed in HGSOC patients (pts) who received prior 1-2L of TIT (if prior 2L, &ge;12m of time interval between 2L; and &ge;3m of time interval from the last TIT to CBP-1008 first dose). The ORR is 48.3%(14/29) and DCR is 82.8%(24/29), regardless of FR expression."	Folate receptor &alpha; (FR&alpha;) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class (FIC) bi-specific ligand drug conjugate targeting FR&alpha; and TRPV6 carrying monomethyl auristatin E (MMAE) as payload.
REF00326	PDC_00366	Ovarian cancer	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate(ORR)	48.30%	%	.	.	.	29 platinum-resistant ovarian cancer patients.	.	.	.	.	.	0.15 mg/kg	.	"Promising efficacy was observed in HGSOC patients (pts) who received prior 1-2L of TIT (if prior 2L, &ge;12m of time interval between 2L; and &ge;3m of time interval from the last TIT to CBP-1008 first dose). The ORR is 48.3%(14/29) and DCR is 82.8%(24/29), regardless of FR expression."	Folate receptor &alpha; (FR&alpha;) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class (FIC) bi-specific ligand drug conjugate targeting FR&alpha; and TRPV6 carrying monomethyl auristatin E (MMAE) as payload.
REF00326	PDC_00366	Ovarian cancer	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	82.80%	%	.	.	.	29 platinum-resistant ovarian cancer patients.	.	.	.	.	.	0.15 mg/kg	.	"Promising efficacy was observed in HGSOC patients (pts) who received prior 1-2L of TIT (if prior 2L, &ge;12m of time interval between 2L; and &ge;3m of time interval from the last TIT to CBP-1008 first dose). The ORR is 48.3%(14/29) and DCR is 82.8%(24/29), regardless of FR expression."	Folate receptor &alpha; (FR&alpha;) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class (FIC) bi-specific ligand drug conjugate targeting FR&alpha; and TRPV6 carrying monomethyl auristatin E (MMAE) as payload.
REF00326	PDC_00366	Ovarian clear cell carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	31.30%	%	.	.	.	16 platinum-resistant ovarian clear cell carcinoma patients.	.	.	.	.	.	0.15 mg/kg	.	"OCCC accounts for 5% to 25% of OC1, and current treatment options have very poor ORR of <10%. The ORR of CBP-1008 (0.15 or 0.17 mg/kg) for OCCC patients was 31.3% (5/16), regardless of FR expression."	Folate receptor &alpha; (FR&alpha;) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class (FIC) bi-specific ligand drug conjugate targeting FR&alpha; and TRPV6 carrying monomethyl auristatin E (MMAE) as payload.
REF00326	PDC_00366	Ovarian clear cell carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD) 	31.30%	%	.	.	.	16 platinum-resistant ovarian clear cell carcinoma patients.	.	.	.	.	.	0.15 mg/kg	.	"OCCC accounts for 5% to 25% of OC1, and current treatment options have very poor ORR of <10%. The ORR of CBP-1008 (0.15 or 0.17 mg/kg) for OCCC patients was 31.3% (5/16), regardless of FR expression."	Folate receptor &alpha; (FR&alpha;) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class (FIC) bi-specific ligand drug conjugate targeting FR&alpha; and TRPV6 carrying monomethyl auristatin E (MMAE) as payload.
REF00326	PDC_00366	Ovarian clear cell carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Progressive disease (PD)	37.40%	%	.	.	.	16 platinum-resistant ovarian clear cell carcinoma patients.	.	.	.	.	.	0.15 mg/kg	.	"OCCC accounts for 5% to 25% of OC1, and current treatment options have very poor ORR of <10%. The ORR of CBP-1008 (0.15 or 0.17 mg/kg) for OCCC patients was 31.3% (5/16), regardless of FR expression."	Folate receptor &alpha; (FR&alpha;) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class (FIC) bi-specific ligand drug conjugate targeting FR&alpha; and TRPV6 carrying monomethyl auristatin E (MMAE) as payload.
REF00326	PDC_00366	Ovarian clear cell carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Objective response rate(ORR)	31.30%	%	.	.	.	16 platinum-resistant ovarian clear cell carcinoma patients.	.	.	.	.	.	0.15 mg/kg	.	"OCCC accounts for 5% to 25% of OC1, and current treatment options have very poor ORR of <10%. The ORR of CBP-1008 (0.15 or 0.17 mg/kg) for OCCC patients was 31.3% (5/16), regardless of FR expression."	Folate receptor &alpha; (FR&alpha;) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class (FIC) bi-specific ligand drug conjugate targeting FR&alpha; and TRPV6 carrying monomethyl auristatin E (MMAE) as payload.
REF00326	PDC_00366	Ovarian clear cell carcinoma	.	Identified from the Human Clinical Data	High Expreesion	Disease control rate (DCR)	62.50%	%	.	.	.	16 platinum-resistant ovarian clear cell carcinoma patients.	.	.	.	.	.	0.15 mg/kg	.	"OCCC accounts for 5% to 25% of OC1, and current treatment options have very poor ORR of <10%. The ORR of CBP-1008 (0.15 or 0.17 mg/kg) for OCCC patients was 31.3% (5/16), regardless of FR expression."	Folate receptor &alpha; (FR&alpha;) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class (FIC) bi-specific ligand drug conjugate targeting FR&alpha; and TRPV6 carrying monomethyl auristatin E (MMAE) as payload.
REF00325	PDC_00367	Solid tumor	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 treatment-emergent adverse event rate	75%	%	.	.	.	"20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma)."	.	.	0.54-1.15 h	.	4 week	0.03 mg/kg	.	"As of 27 April 2023, 20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma) were enrolled at 6 dose levels (DLs). No DLTs or drug-related deaths were observed. For 15 patients (75%) experienced treatment-related adverse events (TRAEs) &ge; grade 3, most common were neutrophil decrease (50%), WBC decrease (40%), hypokalemia (10%) and hypertriglyceridaemia (10%). Among 17 evaluable mCRPC patients, 5 SD and 7 Non-PD were observed with 9 patients delayed administration and 6 patients dropped for Covid-19. Prostate-specific antigen (PSA) 50% decrease was detected in 2 patients. The median PFS was 9.2 months (95%CI, 1.7-9.2) in mCRPC patients. For PK profile of CBP-1018 and free MMAE, t1/2z was ranged 0.54-1.15 h and 38.27-57.27 h, respectively, no accumulation of both substances after multiple doses."	Prostate-specific membrane antigen (PSMA) is highly expressed on prostate cancer and folate receptor &alpha; (FR&alpha;) overexpressed in various malignant tissues which both related to tumor invasiveness. CBP-1018 is a first-in-class bi-ligand-drug conjugate targeting both PSMA and FR&alpha; with monomethyl auristatin E (MMAE) as payload.
REF00325	PDC_00367	Solid tumor	.	Identified from the Human Clinical Data	High Expreesion	Neutrophil decrease	50%	%	.	.	.	"20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma)."	.	.	0.54-1.15 h	.	4 week	0.03 mg/kg	.	"As of 27 April 2023, 20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma) were enrolled at 6 dose levels (DLs). No DLTs or drug-related deaths were observed. For 15 patients (75%) experienced treatment-related adverse events (TRAEs) &ge; grade 3, most common were neutrophil decrease (50%), WBC decrease (40%), hypokalemia (10%) and hypertriglyceridaemia (10%). Among 17 evaluable mCRPC patients, 5 SD and 7 Non-PD were observed with 9 patients delayed administration and 6 patients dropped for Covid-19. Prostate-specific antigen (PSA) 50% decrease was detected in 2 patients. The median PFS was 9.2 months (95%CI, 1.7-9.2) in mCRPC patients. For PK profile of CBP-1018 and free MMAE, t1/2z was ranged 0.54-1.15 h and 38.27-57.27 h, respectively, no accumulation of both substances after multiple doses."	Prostate-specific membrane antigen (PSMA) is highly expressed on prostate cancer and folate receptor &alpha; (FR&alpha;) overexpressed in various malignant tissues which both related to tumor invasiveness. CBP-1018 is a first-in-class bi-ligand-drug conjugate targeting both PSMA and FR&alpha; with monomethyl auristatin E (MMAE) as payload.
REF00325	PDC_00367	Solid tumor	.	Identified from the Human Clinical Data	High Expreesion	WBC decrease	40%	%	.	.	.	"20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma)."	.	.	0.54-1.15 h	.	4 week	0.03 mg/kg	.	"As of 27 April 2023, 20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma) were enrolled at 6 dose levels (DLs). No DLTs or drug-related deaths were observed. For 15 patients (75%) experienced treatment-related adverse events (TRAEs) &ge; grade 3, most common were neutrophil decrease (50%), WBC decrease (40%), hypokalemia (10%) and hypertriglyceridaemia (10%). Among 17 evaluable mCRPC patients, 5 SD and 7 Non-PD were observed with 9 patients delayed administration and 6 patients dropped for Covid-19. Prostate-specific antigen (PSA) 50% decrease was detected in 2 patients. The median PFS was 9.2 months (95%CI, 1.7-9.2) in mCRPC patients. For PK profile of CBP-1018 and free MMAE, t1/2z was ranged 0.54-1.15 h and 38.27-57.27 h, respectively, no accumulation of both substances after multiple doses."	Prostate-specific membrane antigen (PSMA) is highly expressed on prostate cancer and folate receptor &alpha; (FR&alpha;) overexpressed in various malignant tissues which both related to tumor invasiveness. CBP-1018 is a first-in-class bi-ligand-drug conjugate targeting both PSMA and FR&alpha; with monomethyl auristatin E (MMAE) as payload.
REF00325	PDC_00367	Solid tumor	.	Identified from the Human Clinical Data	High Expreesion	Hypokalemia	10%	%	.	.	.	"20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma)."	.	.	0.54-1.15 h	.	4 week	0.03 mg/kg	.	"As of 27 April 2023, 20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma) were enrolled at 6 dose levels (DLs). No DLTs or drug-related deaths were observed. For 15 patients (75%) experienced treatment-related adverse events (TRAEs) &ge; grade 3, most common were neutrophil decrease (50%), WBC decrease (40%), hypokalemia (10%) and hypertriglyceridaemia (10%). Among 17 evaluable mCRPC patients, 5 SD and 7 Non-PD were observed with 9 patients delayed administration and 6 patients dropped for Covid-19. Prostate-specific antigen (PSA) 50% decrease was detected in 2 patients. The median PFS was 9.2 months (95%CI, 1.7-9.2) in mCRPC patients. For PK profile of CBP-1018 and free MMAE, t1/2z was ranged 0.54-1.15 h and 38.27-57.27 h, respectively, no accumulation of both substances after multiple doses."	Prostate-specific membrane antigen (PSMA) is highly expressed on prostate cancer and folate receptor &alpha; (FR&alpha;) overexpressed in various malignant tissues which both related to tumor invasiveness. CBP-1018 is a first-in-class bi-ligand-drug conjugate targeting both PSMA and FR&alpha; with monomethyl auristatin E (MMAE) as payload.
REF00325	PDC_00367	Solid tumor	.	Identified from the Human Clinical Data	High Expreesion	Hypertriglyceridaemia	10%	%	.	.	.	"20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma)."	.	.	0.54-1.15 h	.	4 week	0.03 mg/kg	.	"As of 27 April 2023, 20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma) were enrolled at 6 dose levels (DLs). No DLTs or drug-related deaths were observed. For 15 patients (75%) experienced treatment-related adverse events (TRAEs) &ge; grade 3, most common were neutrophil decrease (50%), WBC decrease (40%), hypokalemia (10%) and hypertriglyceridaemia (10%). Among 17 evaluable mCRPC patients, 5 SD and 7 Non-PD were observed with 9 patients delayed administration and 6 patients dropped for Covid-19. Prostate-specific antigen (PSA) 50% decrease was detected in 2 patients. The median PFS was 9.2 months (95%CI, 1.7-9.2) in mCRPC patients. For PK profile of CBP-1018 and free MMAE, t1/2z was ranged 0.54-1.15 h and 38.27-57.27 h, respectively, no accumulation of both substances after multiple doses."	Prostate-specific membrane antigen (PSMA) is highly expressed on prostate cancer and folate receptor &alpha; (FR&alpha;) overexpressed in various malignant tissues which both related to tumor invasiveness. CBP-1018 is a first-in-class bi-ligand-drug conjugate targeting both PSMA and FR&alpha; with monomethyl auristatin E (MMAE) as payload.
REF00325	PDC_00367	Solid tumor	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD) 	29.40%	%	.	.	.	"20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma)."	.	.	0.54-1.15 h	.	4 week	0.03 mg/kg	.	"As of 27 April 2023, 20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma) were enrolled at 6 dose levels (DLs). No DLTs or drug-related deaths were observed. For 15 patients (75%) experienced treatment-related adverse events (TRAEs) &ge; grade 3, most common were neutrophil decrease (50%), WBC decrease (40%), hypokalemia (10%) and hypertriglyceridaemia (10%). Among 17 evaluable mCRPC patients, 5 SD and 7 Non-PD were observed with 9 patients delayed administration and 6 patients dropped for Covid-19. Prostate-specific antigen (PSA) 50% decrease was detected in 2 patients. The median PFS was 9.2 months (95%CI, 1.7-9.2) in mCRPC patients. For PK profile of CBP-1018 and free MMAE, t1/2z was ranged 0.54-1.15 h and 38.27-57.27 h, respectively, no accumulation of both substances after multiple doses."	Prostate-specific membrane antigen (PSMA) is highly expressed on prostate cancer and folate receptor &alpha; (FR&alpha;) overexpressed in various malignant tissues which both related to tumor invasiveness. CBP-1018 is a first-in-class bi-ligand-drug conjugate targeting both PSMA and FR&alpha; with monomethyl auristatin E (MMAE) as payload.
REF00325	PDC_00367	Solid tumor	.	Identified from the Human Clinical Data	High Expreesion	Non-progressive disease (Non-PD)	41.10%	%	.	.	.	"20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma)."	.	.	0.54-1.15 h	.	4 week	0.03 mg/kg	.	"As of 27 April 2023, 20 patients (18 mCRPC, 1 bladder cancer and 1 ureteral carcinoma) were enrolled at 6 dose levels (DLs). No DLTs or drug-related deaths were observed. For 15 patients (75%) experienced treatment-related adverse events (TRAEs) &ge; grade 3, most common were neutrophil decrease (50%), WBC decrease (40%), hypokalemia (10%) and hypertriglyceridaemia (10%). Among 17 evaluable mCRPC patients, 5 SD and 7 Non-PD were observed with 9 patients delayed administration and 6 patients dropped for Covid-19. Prostate-specific antigen (PSA) 50% decrease was detected in 2 patients. The median PFS was 9.2 months (95%CI, 1.7-9.2) in mCRPC patients. For PK profile of CBP-1018 and free MMAE, t1/2z was ranged 0.54-1.15 h and 38.27-57.27 h, respectively, no accumulation of both substances after multiple doses."	Prostate-specific membrane antigen (PSMA) is highly expressed on prostate cancer and folate receptor &alpha; (FR&alpha;) overexpressed in various malignant tissues which both related to tumor invasiveness. CBP-1018 is a first-in-class bi-ligand-drug conjugate targeting both PSMA and FR&alpha; with monomethyl auristatin E (MMAE) as payload.
REF00321	PDC_00368	Colon adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	1.83 &plusmn; 0.09 &mu;M	&mu;M	.	.	.	.	Colon cancer	HT29 cell	.	.	.	.	Graph Pad Prism 5.0	"Compared with irinotecan and NKTR-102, compound BGC0222 exhibited better antiproliferative activity in all these assayed cell lines. In the antiproliferative activity assay with the HT29 cell line, compound BGC0222 displayed higher antiproliferative activity than irinotecan (IC50 = 7.64 0.19 &mu;M) and NKTR-102 (IC50 = 2.02 0.10 &mu;M), with IC50 value of 1.83 0.09 &mu;M. In addition, compound BGC0222 showed better antiproliferative activity than irinotecan (IC50 = 16.2 0.22 &mu;M) and NKTR-102 (IC50 = 4.68 0.15 &mu;M) against MIA PaCa-2 cells line, with IC50 value of 3.95 0.16 &mu;M, while compound BGC0222 also exhibited stronger antiproliferative activity than irinotecan (IC50 = 2.69 0.12 &mu;M) and NKTR-102 (IC50 = 0.71 0.05 &mu;M) in MCF-7 cells line assay, with IC50 value of 0.68 0.04 &mu;M, respectively. Clearly, the order of in vitro antiproliferative effect against the assay cell lines was: BGC0222>NKTR-102 > irinotecan. The structure-activity relationship was then investigated. The success of NKTR-102 proved that the introducing of PEG should lead to better antiproliferative activity. In addition, by the comparison of the structure of BGC0222 with that of NKTR-102, it should be found the presence of cRGD lead to better antiproliferative effect. Therefore, based on the above observation, it could be concluded that the introduction of PEG and cRGD to irinotecan should efficiently improve the antiproliferative effect, consistent with our expectation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Pancreatic ductal adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	3.95 &plusmn; 0.16 &mu;M	&mu;M	.	.	.	.	Pancreatic ductal adenocarcinoma	MIA PaCa-2 cell	.	.	.	.	Graph Pad Prism 5.0	"Compared with irinotecan and NKTR-102, compound BGC0222 exhibited better antiproliferative activity in all these assayed cell lines. In the antiproliferative activity assay with the HT29 cell line, compound BGC0222 displayed higher antiproliferative activity than irinotecan (IC50 = 7.64 0.19 &mu;M) and NKTR-102 (IC50 = 2.02 0.10 &mu;M), with IC50 value of 1.83 0.09 &mu;M. In addition, compound BGC0222 showed better antiproliferative activity than irinotecan (IC50 = 16.2 0.22 &mu;M) and NKTR-102 (IC50 = 4.68 0.15 &mu;M) against MIA PaCa-2 cells line, with IC50 value of 3.95 0.16 &mu;M, while compound BGC0222 also exhibited stronger antiproliferative activity than irinotecan (IC50 = 2.69 0.12 &mu;M) and NKTR-102 (IC50 = 0.71 0.05 &mu;M) in MCF-7 cells line assay, with IC50 value of 0.68 0.04 &mu;M, respectively. Clearly, the order of in vitro antiproliferative effect against the assay cell lines was: BGC0222>NKTR-102 > irinotecan. The structure-activity relationship was then investigated. The success of NKTR-102 proved that the introducing of PEG should lead to better antiproliferative activity. In addition, by the comparison of the structure of BGC0222 with that of NKTR-102, it should be found the presence of cRGD lead to better antiproliferative effect. Therefore, based on the above observation, it could be concluded that the introduction of PEG and cRGD to irinotecan should efficiently improve the antiproliferative effect, consistent with our expectation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	0.68 &plusmn; 0.04 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	Graph Pad Prism 5.0	"Compared with irinotecan and NKTR-102, compound BGC0222 exhibited better antiproliferative activity in all these assayed cell lines. In the antiproliferative activity assay with the HT29 cell line, compound BGC0222 displayed higher antiproliferative activity than irinotecan (IC50 = 7.64 0.19 &mu;M) and NKTR-102 (IC50 = 2.02 0.10 &mu;M), with IC50 value of 1.83 0.09 &mu;M. In addition, compound BGC0222 showed better antiproliferative activity than irinotecan (IC50 = 16.2 0.22 &mu;M) and NKTR-102 (IC50 = 4.68 0.15 &mu;M) against MIA PaCa-2 cells line, with IC50 value of 3.95 0.16 &mu;M, while compound BGC0222 also exhibited stronger antiproliferative activity than irinotecan (IC50 = 2.69 0.12 &mu;M) and NKTR-102 (IC50 = 0.71 0.05 &mu;M) in MCF-7 cells line assay, with IC50 value of 0.68 0.04 &mu;M, respectively. Clearly, the order of in vitro antiproliferative effect against the assay cell lines was: BGC0222>NKTR-102 > irinotecan. The structure-activity relationship was then investigated. The success of NKTR-102 proved that the introducing of PEG should lead to better antiproliferative activity. In addition, by the comparison of the structure of BGC0222 with that of NKTR-102, it should be found the presence of cRGD lead to better antiproliferative effect. Therefore, based on the above observation, it could be concluded that the introduction of PEG and cRGD to irinotecan should efficiently improve the antiproliferative effect, consistent with our expectation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Relative tumor volume (RTV)	1	.	.	.	.	.	Colon cancer	HT29 cell	.	.	12 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Relative tumor volume (RTV)	1.47	.	.	.	.	.	Colon cancer	HT29 cell	.	.	15 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Relative tumor volume (RTV)	1.56	.	.	.	.	.	Colon cancer	HT29 cell	.	.	18 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Relative tumor volume (RTV)	1.15	.	.	.	.	.	Colon cancer	HT29 cell	.	.	22 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Relative tumor volume (RTV)	0.88	.	.	.	.	.	Colon cancer	HT29 cell	.	.	25 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Relative tumor volume (RTV)	0.72	.	.	.	.	.	Colon cancer	HT29 cell	.	.	29 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Relative tumor volume (RTV)	0.82	.	.	.	.	.	Colon cancer	HT29 cell	.	.	32 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor increment rates values	100%	%	.	.	.	.	Colon cancer	HT29 cell	.	.	12 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor increment rates values	88.80%	%	.	.	.	.	Colon cancer	HT29 cell	.	.	15 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor increment rates values	57.00%	%	.	.	.	.	Colon cancer	HT29 cell	.	.	18 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor increment rates values	27.60%	%	.	.	.	.	Colon cancer	HT29 cell	.	.	22 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor increment rates values	16.90%	%	.	.	.	.	Colon cancer	HT29 cell	.	.	25 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor increment rates values	9.87%	%	.	.	.	.	Colon cancer	HT29 cell	.	.	29 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor increment rates values	9.21%	%	.	.	.	.	Colon cancer	HT29 cell	.	.	32 days	"40 mg/kg, Q4D3"	.	"BGC0222 exhibited remarkable inhibition on HT-29 tumor growth. Firstly, for BGC0222, the RTV values of days 12, 15, 18, 22, 25, 29 and 32 were found to be 1.00, 1.47, 1.56, 1.15, 0.88, 0.72, 0.82, while that of irinotecan and NKTR-102 were found to be 1.00, 1.71, 2.54, 3.13, 3.60, 4.43, 6.31 and 1.00, 1.59, 1.91, 2.14, 2.03, 2.07, 2.41, respectivel. Evidently, the RTV values of BGC0222 were much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100X300 mm3 (after day 12), indicating that the in vivo antitumor activity of BGC0222 was obviously better than that of irinotecan and NKTR-102. In addition, as shown in Tables S31, T/C values of BGC0222 for days 12, 15, 18, 22, 25, 29 and 32 were determined to be 100%, 88.8%, 57.0%, 27.6%, 16.9%, 9.87% and 9.21%, while that of irinotecan and NKTR-102 were found to be 100%, 103%, 93.1%, 75.1%, 68.8%, 60.6%, 71.1% and 100%, 96.0%, 70.0%, 51.3%, 38.7%, 28.3%, 27.2%, respectively. Clearly, the T/C values of BGC0222 were also much lower than that of irinotecan and NKTR-102 when the average tumor size reached approximately 100300 mm3, demonstrating that its' in vivo antitumor activity was better than that of irinotecan and NKTR-102. This result was consistent with that of RTV assay. These in vivo results indicated that BGC0222 exhibited higher antitumor effect than irinotecan and NKTR-102 at the same condition in the HT-29 mouse model, consistent with the results of the in vitro cytotoxicity assay. It should be important to note that no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222, indicating that BGC0222 displayed no significant toxicity to the mice within the period of treatment. It was obvious that the weight change range of the mice treated with irinotecan was bigger than that of BGC0222, impling that the toxicity of BGC0222 may be lower than that of irinotecan, consistent with that in preliminary safety evaluation."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Colon adenocarcinoma	Female Balb/c nude mouse HT-29 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	90%	%	.	.	.	.	Colon cancer	HT29 cell	.	.	32 days	"40 mg/kg, Q4D3"	.	"It was worth noting that, similar with that in HT-29 mice model, as shown in Fig. 3, BGC0222 also exhibited better antitumor effect than irinotecan and NKTR-102 in MIA PaCa-2(B), NCI-H446(C), U-87 MG(D) and MDA-MB-231(E) xenograft models, with lower RTV and T/C values. Moreover, in these model assays, there were also no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Pancreatic ductal adenocarcinoma	Female Balb/c nude mouse MIA PaCa-2 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	98%	%	.	.	.	.	Pancreatic ductal adenocarcinoma	MIA PaCa-2 cell	.	.	31 days	"20 mg/kg, QW3"	.	"It was worth noting that, similar with that in HT-29 mice model, as shown in Fig. 3, BGC0222 also exhibited better antitumor effect than irinotecan and NKTR-102 in MIA PaCa-2(B), NCI-H446(C), U-87 MG(D) and MDA-MB-231(E) xenograft models, with lower RTV and T/C values. Moreover, in these model assays, there were also no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Small cell lung cancer	Female Balb/c nude mouse NCI-H446 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	95%	%	.	.	.	.	Lung small cell carcinoma	NCI-H446 cell	.	.	30 days	"20 mg/kg, QW3"	.	"It was worth noting that, similar with that in HT-29 mice model, as shown in Fig. 3, BGC0222 also exhibited better antitumor effect than irinotecan and NKTR-102 in MIA PaCa-2(B), NCI-H446(C), U-87 MG(D) and MDA-MB-231(E) xenograft models, with lower RTV and T/C values. Moreover, in these model assays, there were also no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Glioblastoma	Female Balb/c nude mouse U-87MG cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	94%	%	.	.	.	.	Glioblastoma	U-87MG cell	.	.	40 days	"60 mg/kg, QW3"	.	"It was worth noting that, similar with that in HT-29 mice model, as shown in Fig. 3, BGC0222 also exhibited better antitumor effect than irinotecan and NKTR-102 in MIA PaCa-2(B), NCI-H446(C), U-87 MG(D) and MDA-MB-231(E) xenograft models, with lower RTV and T/C values. Moreover, in these model assays, there were also no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00321	PDC_00368	Breast cancer	Female Balb/c nude mouse MDA-MB-231 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	99%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	36 days	"20 mg/kg, Q4D3"	.	"It was worth noting that, similar with that in HT-29 mice model, as shown in Fig. 3, BGC0222 also exhibited better antitumor effect than irinotecan and NKTR-102 in MIA PaCa-2(B), NCI-H446(C), U-87 MG(D) and MDA-MB-231(E) xenograft models, with lower RTV and T/C values. Moreover, in these model assays, there were also no significant change in body weight and no other adverse effects were observed among the mice treated with BGC0222."	"As a semisynthetic analog of camptothecin (CPT), irinotecan is a well-known topoisomerase 1 (Top1) inhibitor and widely used chemotherapeutic agent. In order to increase the antitumor efficiency and low solubility and reduce the toxicity of irinotecan, the PEG-conjugated irinotecan derivative etirinotecan pegol (NKTR-102), which contains a 4-arm PEG polymer, a hydrolysable ester-based linker, and one irinotecan molecule at the end of each arm, has been designed and developed by Nektar Therapeutics. Study has demonstrated that NKTR-102 shows improved drug penetration into tumors leading to improved efficacy over irinotecan in a series of mouse models of human cancers, and it even exhibits a good result in phase II clinical trial, indicating that PEGylation of irinotecan is a feasible method to improve the antitumor activity and toxicity, though the phase III study fails to meet its prespecified response rate endpoint. However, the failure of the phase III study of NKTR-102 seems to demonstrate that the extent of passive tumor-targeting alone by enhanced permeation and retention of PEGylation is still limited. It is assumed that the further modification of NKTR-102 with active targeted moiety may lead to better efficiency and lower toxicity. The arginine-glycine-aspartic acid (RGD) peptide is a cell adhesion motif that can forwardly interact efficiently with the overexpressed integrin receptors (mainly &alpha;v3), which plays a major role in tumor-induced angiogenesis, tumor neovascularization, and tumor metastasis. Moreover, cyclic RGD (cRGD) peptide, which has been proven to be a more efficient tumor-targeting ligand in comparison with linear RGD peptide, has been widely used for the delivery of anticancer drugs to tumors. Previous work had demonstrated that the introduction of cRGD peptide to CPT scaffold may effectively improve the antitumor activity, receptor affinity (mainly &alpha;v3) and tumor cell adhesion. Herein, inspiring by the structure of NKTR-102, PEG linker was used as passive tumor targeting ligand to functionalize irinotecan (CPT derivative), while cRGD was designed as active tumor targeting moiety. It is expected that the combination of PEGylation and cRGD may lead to better enhanced permeation and retention, which may result to better efficiency and lower toxicity of irinotecan. Therefore, in the present work, a novel PEG-cRGD-conjugated irinotecan derivative was designed and synthesized. However, to the best of our knowledge, irinotecan simultaneously elaborated with cRGD and PEGylation has not been reported. The in vivo and in vitro antitumor activities, as well as the preliminary safety were also evaluated. Furthermore, integrin-binding competition between recombinant human &alpha;v3 and &alpha;v5 integrin, as well as chick chorioallantoic membrane (CAM) angiogenesis assays were carried out to evaluated the action mechanism. Finally, preliminary pharmacokinetic study of the PEG-cRGD-conjugated irinotecan derivative in the whole blood was performed."
REF00322	PDC_00371	Neuroendocrine neoplasms	.	Identified from the Human Clinical Data	High Expreesion	PET75% overall sensitivity	100%	%	.	.	.	38 patients with NEN.	.	.	.	.	.	142 MBq	PET/CT	"The median [64Cu]Cu-DOTATATE activity dose could be reduced from 191 to 142 MBq without decline in diagnostic image quality (P = 0.62), diagnostic lesion confidence (P = 1.0), or number of lesions detected in major organs or regions (P = 0.19-0.71). Sensitivity and specificity for detection of liver disease were 100% (26/26 patients) and 100% (12/12), respectively, for both PET75% and PET50%. Overall sensitivity for detection of NEN was 100% (26/26) for both PET75% and PET50%, and overall specificities were 92% (11/12) and 100% (12/12) for PET75 and PET50, respectively. Following dose-blinded post hoc review, the PET75% specificity was adjusted to 100% (12/12)."	"Somatostatin analogues radiolabeled with the radioisotope 68Ga, e.g. [68Ga]Ga-DOTATATE and [68Ga]Ga-DOTATOC, are currently the predominately used tracers for PET imaging of patients with NEN. However, the 64Cu-labeled SSR targeting somatostatin analogue [64Cu]Cu-DOTATATE is emerging as an alternative to 68Ga-labeled radiotracers. Although 64Cu has a lower branching ratio for + decay than 68Ga (18% vs 89%), 64Cu has the advantage of a longer half-life (12.7 h vs 68 min) and shorter positron range (0.7 mm vs 3.5 mm) where the latter at least in theory should lead to better spatial resolution. The effective whole-body dose is 6.3 mSv for a 200 MBq injection of [64Cu]Cu-DOTATATE or 4.7 mSv for the United States Food and Drug Administration (FDA) recommended dose of 148 MBq."
REF00322	PDC_00371	Neuroendocrine neoplasms	.	Identified from the Human Clinical Data	High Expreesion	PET50% overall sensitivity	100%	%	.	.	.	38 patients with NEN.	.	.	.	.	.	142 MBq	PET/CT	"The median [64Cu]Cu-DOTATATE activity dose could be reduced from 191 to 142 MBq without decline in diagnostic image quality (P = 0.62), diagnostic lesion confidence (P = 1.0), or number of lesions detected in major organs or regions (P = 0.19-0.71). Sensitivity and specificity for detection of liver disease were 100% (26/26 patients) and 100% (12/12), respectively, for both PET75% and PET50%. Overall sensitivity for detection of NEN was 100% (26/26) for both PET75% and PET50%, and overall specificities were 92% (11/12) and 100% (12/12) for PET75 and PET50, respectively. Following dose-blinded post hoc review, the PET75% specificity was adjusted to 100% (12/12)."	"Somatostatin analogues radiolabeled with the radioisotope 68Ga, e.g. [68Ga]Ga-DOTATATE and [68Ga]Ga-DOTATOC, are currently the predominately used tracers for PET imaging of patients with NEN. However, the 64Cu-labeled SSR targeting somatostatin analogue [64Cu]Cu-DOTATATE is emerging as an alternative to 68Ga-labeled radiotracers. Although 64Cu has a lower branching ratio for + decay than 68Ga (18% vs 89%), 64Cu has the advantage of a longer half-life (12.7 h vs 68 min) and shorter positron range (0.7 mm vs 3.5 mm) where the latter at least in theory should lead to better spatial resolution. The effective whole-body dose is 6.3 mSv for a 200 MBq injection of [64Cu]Cu-DOTATATE or 4.7 mSv for the United States Food and Drug Administration (FDA) recommended dose of 148 MBq."
REF00322	PDC_00371	Neuroendocrine neoplasms	.	Identified from the Human Clinical Data	High Expreesion	PET75% overall specificities	92%	%	.	.	.	38 patients with NEN.	.	.	.	.	.	142 MBq	PET/CT	"The median [64Cu]Cu-DOTATATE activity dose could be reduced from 191 to 142 MBq without decline in diagnostic image quality (P = 0.62), diagnostic lesion confidence (P = 1.0), or number of lesions detected in major organs or regions (P = 0.19-0.71). Sensitivity and specificity for detection of liver disease were 100% (26/26 patients) and 100% (12/12), respectively, for both PET75% and PET50%. Overall sensitivity for detection of NEN was 100% (26/26) for both PET75% and PET50%, and overall specificities were 92% (11/12) and 100% (12/12) for PET75 and PET50, respectively. Following dose-blinded post hoc review, the PET75% specificity was adjusted to 100% (12/12)."	"Somatostatin analogues radiolabeled with the radioisotope 68Ga, e.g. [68Ga]Ga-DOTATATE and [68Ga]Ga-DOTATOC, are currently the predominately used tracers for PET imaging of patients with NEN. However, the 64Cu-labeled SSR targeting somatostatin analogue [64Cu]Cu-DOTATATE is emerging as an alternative to 68Ga-labeled radiotracers. Although 64Cu has a lower branching ratio for + decay than 68Ga (18% vs 89%), 64Cu has the advantage of a longer half-life (12.7 h vs 68 min) and shorter positron range (0.7 mm vs 3.5 mm) where the latter at least in theory should lead to better spatial resolution. The effective whole-body dose is 6.3 mSv for a 200 MBq injection of [64Cu]Cu-DOTATATE or 4.7 mSv for the United States Food and Drug Administration (FDA) recommended dose of 148 MBq."
REF00322	PDC_00371	Neuroendocrine neoplasms	.	Identified from the Human Clinical Data	High Expreesion	PET50% overall specificities	100%	%	.	.	.	38 patients with NEN.	.	.	.	.	.	142 MBq	PET/CT	"The median [64Cu]Cu-DOTATATE activity dose could be reduced from 191 to 142 MBq without decline in diagnostic image quality (P = 0.62), diagnostic lesion confidence (P = 1.0), or number of lesions detected in major organs or regions (P = 0.19-0.71). Sensitivity and specificity for detection of liver disease were 100% (26/26 patients) and 100% (12/12), respectively, for both PET75% and PET50%. Overall sensitivity for detection of NEN was 100% (26/26) for both PET75% and PET50%, and overall specificities were 92% (11/12) and 100% (12/12) for PET75 and PET50, respectively. Following dose-blinded post hoc review, the PET75% specificity was adjusted to 100% (12/12)."	"Somatostatin analogues radiolabeled with the radioisotope 68Ga, e.g. [68Ga]Ga-DOTATATE and [68Ga]Ga-DOTATOC, are currently the predominately used tracers for PET imaging of patients with NEN. However, the 64Cu-labeled SSR targeting somatostatin analogue [64Cu]Cu-DOTATATE is emerging as an alternative to 68Ga-labeled radiotracers. Although 64Cu has a lower branching ratio for + decay than 68Ga (18% vs 89%), 64Cu has the advantage of a longer half-life (12.7 h vs 68 min) and shorter positron range (0.7 mm vs 3.5 mm) where the latter at least in theory should lead to better spatial resolution. The effective whole-body dose is 6.3 mSv for a 200 MBq injection of [64Cu]Cu-DOTATATE or 4.7 mSv for the United States Food and Drug Administration (FDA) recommended dose of 148 MBq."
REF00605	PDC_02015	Prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Sensitivity	40%	%	.	.	Phase 3	252 patients with prostate cancer.	.	.	8 h	.	.	8-10 mCi	PET/CT	"Within cohort A, the primary end point was the sensitivity and specificity for detection of metastases to the pelvic lymph nodes by 18F-DCFPyL PET/CT. These findings were validated by histopathology after radical proctectomy and lymph node dissection (Figure 6). When all confirmed positive lymph node metastases were considered, the sensitivity of 18F-DCFPyL PET/CT was 40%, with a 98% specificity. It is perhaps unsurprising that histopathology is more sensitivity for the detection of early metastases as a sufficient number of malignant cells must accumulate before any imaging modality will be positive. However, a post-hoc analysis considering only lesions >5 mm found the sensitivity of 18F-DCFPyL PET/CT increased to 60%. Despite this, across all lesions, 18F-DCFPyL PET/CT significantly outperformed conventional CT pelvic imaging with markedly improved specificity (97.7% vs. 65.1%) and positive predictive value (85.1% vs. 28.3%) for pelvic lymph node metastases, as well as sensitivity for disease within the prostate (96.8% vs. 35.9%)."	"PSMA, also known as glutamate carboxypeptidase 2 or folate hydrolase 1, is highly expressed in nearly all prostate cancers. Structurally, PSMA is a large extracellular carboxypeptidase domain that is tethered to the cellular membrane by a short transmembrane domain. Physiologically, PSMA is also expressed in normal tissue, including non-malignant prostate tissue, the kidney, the small intestine, and the central nervous system. In most tissues, PSMA likely contributes to folate uptake by cleaving the C-terminal glutamate from folic acid (Figure 1). Within the brain, PSMA regulates the level of N-acetylaspartylglutamate (NAAG) by catalyzing its degradation to glutamate. Structure of PSMA substrates and inhibitors. Left: structure of the PSMA substrate folic acid. The peptide bond (dashed box) linking the P1 glutamate residue (blue) to the remainder of the substrate (P1, red) is cleaved by PSMA. Right: Structure of the PSMA-PET agents 18F-DCFPyL and 68Ga-PSMA-11. The scissile peptide bond has been replaced by a non-hydrolyzable urea motif (red) to generate PMSA inhibitors. The P1 glutamate residue is essential for binding to PSMA, but a wide degree of variability is tolerated in the opposing end of the structure."
REF00605	PDC_02015	Prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Sensitivity	96%	%	.	.	Phase 3	93 patients with prostate cancer.	.	.	8 h	.	.	8-10 mCi	PET/CT	"Within cohort A, the primary end point was the sensitivity and specificity for detection of metastases to the pelvic lymph nodes by 18F-DCFPyL PET/CT. These findings were validated by histopathology after radical proctectomy and lymph node dissection (Figure 6). When all confirmed positive lymph node metastases were considered, the sensitivity of 18F-DCFPyL PET/CT was 40%, with a 98% specificity. It is perhaps unsurprising that histopathology is more sensitivity for the detection of early metastases as a sufficient number of malignant cells must accumulate before any imaging modality will be positive. However, a post-hoc analysis considering only lesions >5 mm found the sensitivity of 18F-DCFPyL PET/CT increased to 60%. Despite this, across all lesions, 18F-DCFPyL PET/CT significantly outperformed conventional CT pelvic imaging with markedly improved specificity (97.7% vs. 65.1%) and positive predictive value (85.1% vs. 28.3%) for pelvic lymph node metastases, as well as sensitivity for disease within the prostate (96.8% vs. 35.9%)."	"PSMA, also known as glutamate carboxypeptidase 2 or folate hydrolase 1, is highly expressed in nearly all prostate cancers. Structurally, PSMA is a large extracellular carboxypeptidase domain that is tethered to the cellular membrane by a short transmembrane domain. Physiologically, PSMA is also expressed in normal tissue, including non-malignant prostate tissue, the kidney, the small intestine, and the central nervous system. In most tissues, PSMA likely contributes to folate uptake by cleaving the C-terminal glutamate from folic acid (Figure 1). Within the brain, PSMA regulates the level of N-acetylaspartylglutamate (NAAG) by catalyzing its degradation to glutamate. Structure of PSMA substrates and inhibitors. Left: structure of the PSMA substrate folic acid. The peptide bond (dashed box) linking the P1 glutamate residue (blue) to the remainder of the substrate (P1, red) is cleaved by PSMA. Right: Structure of the PSMA-PET agents 18F-DCFPyL and 68Ga-PSMA-11. The scissile peptide bond has been replaced by a non-hydrolyzable urea motif (red) to generate PMSA inhibitors. The P1 glutamate residue is essential for binding to PSMA, but a wide degree of variability is tolerated in the opposing end of the structure."
REF00605	PDC_02015	Prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Sensitivity	86%	%	.	.	Phase 3	208 patients with prostate cancer.	.	.	8 h	.	.	8-10 mCi	PET/CT	"All patients were dosed with 9 mCi of 18F-DCFPyL and PET/CT images were obtained. 18F-DCFPyL avid lesions were detected in ~60% of the patients. To confirm the metastatic nature of these lesions, biopsies were obtained, if possible. If the lesion was not amendable to biopsy, validation is obtained by focused conventional follow-up imaging or biochemical response to external beam radiotherapy. The differentiation between the number of true metastases validated by other techniques (i.e. true positives, TP) and false positives (FP) allows for the calculation of the correct localization rate (CLR), where the CLR = TP/(TP + FP) * 100 (essentially, PPV with the added requirement of anatomic co-localization). Across all patients, the CLR ranged from 85% to 87% between readers, however the CLR improved as the baseline PSA increased, from 75% to 96% (PSA < 1.0 to PSA &ge; 5.0, respectively). The PPV of the 18F-DCFPyL PET/CT was found to vary by anatomic region and was highest for prostatic lesions (80%) and pelvic lymph nodes (71%), but lower for extrapelvic visceral/soft tissue masses (29%)."	"PSMA, also known as glutamate carboxypeptidase 2 or folate hydrolase 1, is highly expressed in nearly all prostate cancers. Structurally, PSMA is a large extracellular carboxypeptidase domain that is tethered to the cellular membrane by a short transmembrane domain. Physiologically, PSMA is also expressed in normal tissue, including non-malignant prostate tissue, the kidney, the small intestine, and the central nervous system. In most tissues, PSMA likely contributes to folate uptake by cleaving the C-terminal glutamate from folic acid (Figure 1). Within the brain, PSMA regulates the level of N-acetylaspartylglutamate (NAAG) by catalyzing its degradation to glutamate. Structure of PSMA substrates and inhibitors. Left: structure of the PSMA substrate folic acid. The peptide bond (dashed box) linking the P1 glutamate residue (blue) to the remainder of the substrate (P1, red) is cleaved by PSMA. Right: Structure of the PSMA-PET agents 18F-DCFPyL and 68Ga-PSMA-11. The scissile peptide bond has been replaced by a non-hydrolyzable urea motif (red) to generate PMSA inhibitors. The P1 glutamate residue is essential for binding to PSMA, but a wide degree of variability is tolerated in the opposing end of the structure."
REF00605	PDC_02015	Prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Specificity	98%	%	.	.	Phase 3	252 patients with prostate cancer.	.	.	8 h	.	.	8-10 mCi	PET/CT	"Within cohort A, the primary end point was the sensitivity and specificity for detection of metastases to the pelvic lymph nodes by 18F-DCFPyL PET/CT. These findings were validated by histopathology after radical proctectomy and lymph node dissection (Figure 6). When all confirmed positive lymph node metastases were considered, the sensitivity of 18F-DCFPyL PET/CT was 40%, with a 98% specificity. It is perhaps unsurprising that histopathology is more sensitivity for the detection of early metastases as a sufficient number of malignant cells must accumulate before any imaging modality will be positive. However, a post-hoc analysis considering only lesions >5 mm found the sensitivity of 18F-DCFPyL PET/CT increased to 60%. Despite this, across all lesions, 18F-DCFPyL PET/CT significantly outperformed conventional CT pelvic imaging with markedly improved specificity (97.7% vs. 65.1%) and positive predictive value (85.1% vs. 28.3%) for pelvic lymph node metastases, as well as sensitivity for disease within the prostate (96.8% vs. 35.9%)."	"PSMA, also known as glutamate carboxypeptidase 2 or folate hydrolase 1, is highly expressed in nearly all prostate cancers. Structurally, PSMA is a large extracellular carboxypeptidase domain that is tethered to the cellular membrane by a short transmembrane domain. Physiologically, PSMA is also expressed in normal tissue, including non-malignant prostate tissue, the kidney, the small intestine, and the central nervous system. In most tissues, PSMA likely contributes to folate uptake by cleaving the C-terminal glutamate from folic acid (Figure 1). Within the brain, PSMA regulates the level of N-acetylaspartylglutamate (NAAG) by catalyzing its degradation to glutamate. Structure of PSMA substrates and inhibitors. Left: structure of the PSMA substrate folic acid. The peptide bond (dashed box) linking the P1 glutamate residue (blue) to the remainder of the substrate (P1, red) is cleaved by PSMA. Right: Structure of the PSMA-PET agents 18F-DCFPyL and 68Ga-PSMA-11. The scissile peptide bond has been replaced by a non-hydrolyzable urea motif (red) to generate PMSA inhibitors. The P1 glutamate residue is essential for binding to PSMA, but a wide degree of variability is tolerated in the opposing end of the structure."
REF00605	PDC_02015	Prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Negative predictive value	83.00%	%	.	.	Phase 3	252 patients with prostate cancer.	.	.	8 h	.	.	8-10 mCi	PET/CT	"Within cohort A, the primary end point was the sensitivity and specificity for detection of metastases to the pelvic lymph nodes by 18F-DCFPyL PET/CT. These findings were validated by histopathology after radical proctectomy and lymph node dissection (Figure 6). When all confirmed positive lymph node metastases were considered, the sensitivity of 18F-DCFPyL PET/CT was 40%, with a 98% specificity. It is perhaps unsurprising that histopathology is more sensitivity for the detection of early metastases as a sufficient number of malignant cells must accumulate before any imaging modality will be positive. However, a post-hoc analysis considering only lesions >5 mm found the sensitivity of 18F-DCFPyL PET/CT increased to 60%. Despite this, across all lesions, 18F-DCFPyL PET/CT significantly outperformed conventional CT pelvic imaging with markedly improved specificity (97.7% vs. 65.1%) and positive predictive value (85.1% vs. 28.3%) for pelvic lymph node metastases, as well as sensitivity for disease within the prostate (96.8% vs. 35.9%)."	"PSMA, also known as glutamate carboxypeptidase 2 or folate hydrolase 1, is highly expressed in nearly all prostate cancers. Structurally, PSMA is a large extracellular carboxypeptidase domain that is tethered to the cellular membrane by a short transmembrane domain. Physiologically, PSMA is also expressed in normal tissue, including non-malignant prostate tissue, the kidney, the small intestine, and the central nervous system. In most tissues, PSMA likely contributes to folate uptake by cleaving the C-terminal glutamate from folic acid (Figure 1). Within the brain, PSMA regulates the level of N-acetylaspartylglutamate (NAAG) by catalyzing its degradation to glutamate. Structure of PSMA substrates and inhibitors. Left: structure of the PSMA substrate folic acid. The peptide bond (dashed box) linking the P1 glutamate residue (blue) to the remainder of the substrate (P1, red) is cleaved by PSMA. Right: Structure of the PSMA-PET agents 18F-DCFPyL and 68Ga-PSMA-11. The scissile peptide bond has been replaced by a non-hydrolyzable urea motif (red) to generate PMSA inhibitors. The P1 glutamate residue is essential for binding to PSMA, but a wide degree of variability is tolerated in the opposing end of the structure."
REF00605	PDC_02015	Prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Dysgeusia	3%	%	.	.	Phase 3	345 patients with prostate cancer.	.	.	8 h	.	.	8-10 mCi	PET/CT	"Within cohort A, the primary end point was the sensitivity and specificity for detection of metastases to the pelvic lymph nodes by 18F-DCFPyL PET/CT. These findings were validated by histopathology after radical proctectomy and lymph node dissection (Figure 6). When all confirmed positive lymph node metastases were considered, the sensitivity of 18F-DCFPyL PET/CT was 40%, with a 98% specificity. It is perhaps unsurprising that histopathology is more sensitivity for the detection of early metastases as a sufficient number of malignant cells must accumulate before any imaging modality will be positive. However, a post-hoc analysis considering only lesions >5 mm found the sensitivity of 18F-DCFPyL PET/CT increased to 60%. Despite this, across all lesions, 18F-DCFPyL PET/CT significantly outperformed conventional CT pelvic imaging with markedly improved specificity (97.7% vs. 65.1%) and positive predictive value (85.1% vs. 28.3%) for pelvic lymph node metastases, as well as sensitivity for disease within the prostate (96.8% vs. 35.9%)."	"PSMA, also known as glutamate carboxypeptidase 2 or folate hydrolase 1, is highly expressed in nearly all prostate cancers. Structurally, PSMA is a large extracellular carboxypeptidase domain that is tethered to the cellular membrane by a short transmembrane domain. Physiologically, PSMA is also expressed in normal tissue, including non-malignant prostate tissue, the kidney, the small intestine, and the central nervous system. In most tissues, PSMA likely contributes to folate uptake by cleaving the C-terminal glutamate from folic acid (Figure 1). Within the brain, PSMA regulates the level of N-acetylaspartylglutamate (NAAG) by catalyzing its degradation to glutamate. Structure of PSMA substrates and inhibitors. Left: structure of the PSMA substrate folic acid. The peptide bond (dashed box) linking the P1 glutamate residue (blue) to the remainder of the substrate (P1, red) is cleaved by PSMA. Right: Structure of the PSMA-PET agents 18F-DCFPyL and 68Ga-PSMA-11. The scissile peptide bond has been replaced by a non-hydrolyzable urea motif (red) to generate PMSA inhibitors. The P1 glutamate residue is essential for binding to PSMA, but a wide degree of variability is tolerated in the opposing end of the structure."
REF00605	PDC_02015	Prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Headache rate	2%	%	.	.	Phase 3	345 patients with prostate cancer.	.	.	8 h	.	.	8-10 mCi	PET/CT	"Within cohort A, the primary end point was the sensitivity and specificity for detection of metastases to the pelvic lymph nodes by 18F-DCFPyL PET/CT. These findings were validated by histopathology after radical proctectomy and lymph node dissection (Figure 6). When all confirmed positive lymph node metastases were considered, the sensitivity of 18F-DCFPyL PET/CT was 40%, with a 98% specificity. It is perhaps unsurprising that histopathology is more sensitivity for the detection of early metastases as a sufficient number of malignant cells must accumulate before any imaging modality will be positive. However, a post-hoc analysis considering only lesions >5 mm found the sensitivity of 18F-DCFPyL PET/CT increased to 60%. Despite this, across all lesions, 18F-DCFPyL PET/CT significantly outperformed conventional CT pelvic imaging with markedly improved specificity (97.7% vs. 65.1%) and positive predictive value (85.1% vs. 28.3%) for pelvic lymph node metastases, as well as sensitivity for disease within the prostate (96.8% vs. 35.9%)."	"PSMA, also known as glutamate carboxypeptidase 2 or folate hydrolase 1, is highly expressed in nearly all prostate cancers. Structurally, PSMA is a large extracellular carboxypeptidase domain that is tethered to the cellular membrane by a short transmembrane domain. Physiologically, PSMA is also expressed in normal tissue, including non-malignant prostate tissue, the kidney, the small intestine, and the central nervous system. In most tissues, PSMA likely contributes to folate uptake by cleaving the C-terminal glutamate from folic acid (Figure 1). Within the brain, PSMA regulates the level of N-acetylaspartylglutamate (NAAG) by catalyzing its degradation to glutamate. Structure of PSMA substrates and inhibitors. Left: structure of the PSMA substrate folic acid. The peptide bond (dashed box) linking the P1 glutamate residue (blue) to the remainder of the substrate (P1, red) is cleaved by PSMA. Right: Structure of the PSMA-PET agents 18F-DCFPyL and 68Ga-PSMA-11. The scissile peptide bond has been replaced by a non-hydrolyzable urea motif (red) to generate PMSA inhibitors. The P1 glutamate residue is essential for binding to PSMA, but a wide degree of variability is tolerated in the opposing end of the structure."
REF00605	PDC_02015	Prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Fatigue	1%	%	.	.	Phase 3	345 patients with prostate cancer.	.	.	8 h	.	.	8-10 mCi	PET/CT	"Within cohort A, the primary end point was the sensitivity and specificity for detection of metastases to the pelvic lymph nodes by 18F-DCFPyL PET/CT. These findings were validated by histopathology after radical proctectomy and lymph node dissection (Figure 6). When all confirmed positive lymph node metastases were considered, the sensitivity of 18F-DCFPyL PET/CT was 40%, with a 98% specificity. It is perhaps unsurprising that histopathology is more sensitivity for the detection of early metastases as a sufficient number of malignant cells must accumulate before any imaging modality will be positive. However, a post-hoc analysis considering only lesions >5 mm found the sensitivity of 18F-DCFPyL PET/CT increased to 60%. Despite this, across all lesions, 18F-DCFPyL PET/CT significantly outperformed conventional CT pelvic imaging with markedly improved specificity (97.7% vs. 65.1%) and positive predictive value (85.1% vs. 28.3%) for pelvic lymph node metastases, as well as sensitivity for disease within the prostate (96.8% vs. 35.9%)."	"PSMA, also known as glutamate carboxypeptidase 2 or folate hydrolase 1, is highly expressed in nearly all prostate cancers. Structurally, PSMA is a large extracellular carboxypeptidase domain that is tethered to the cellular membrane by a short transmembrane domain. Physiologically, PSMA is also expressed in normal tissue, including non-malignant prostate tissue, the kidney, the small intestine, and the central nervous system. In most tissues, PSMA likely contributes to folate uptake by cleaving the C-terminal glutamate from folic acid (Figure 1). Within the brain, PSMA regulates the level of N-acetylaspartylglutamate (NAAG) by catalyzing its degradation to glutamate. Structure of PSMA substrates and inhibitors. Left: structure of the PSMA substrate folic acid. The peptide bond (dashed box) linking the P1 glutamate residue (blue) to the remainder of the substrate (P1, red) is cleaved by PSMA. Right: Structure of the PSMA-PET agents 18F-DCFPyL and 68Ga-PSMA-11. The scissile peptide bond has been replaced by a non-hydrolyzable urea motif (red) to generate PMSA inhibitors. The P1 glutamate residue is essential for binding to PSMA, but a wide degree of variability is tolerated in the opposing end of the structure."
REF00605	PDC_02015	Prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Headache rate	2%	%	.	.	Phase 3	208 patients with prostate cancer.	.	.	8 h	.	.	8-10 mCi	PET/CT	"All patients were dosed with 9 mCi of 18F-DCFPyL and PET/CT images were obtained. 18F-DCFPyL avid lesions were detected in ~60% of the patients. To confirm the metastatic nature of these lesions, biopsies were obtained, if possible. If the lesion was not amendable to biopsy, validation is obtained by focused conventional follow-up imaging or biochemical response to external beam radiotherapy. The differentiation between the number of true metastases validated by other techniques (i.e. true positives, TP) and false positives (FP) allows for the calculation of the correct localization rate (CLR), where the CLR = TP/(TP + FP) * 100 (essentially, PPV with the added requirement of anatomic co-localization). Across all patients, the CLR ranged from 85% to 87% between readers, however the CLR improved as the baseline PSA increased, from 75% to 96% (PSA < 1.0 to PSA &ge; 5.0, respectively). The PPV of the 18F-DCFPyL PET/CT was found to vary by anatomic region and was highest for prostatic lesions (80%) and pelvic lymph nodes (71%), but lower for extrapelvic visceral/soft tissue masses (29%)."	"PSMA, also known as glutamate carboxypeptidase 2 or folate hydrolase 1, is highly expressed in nearly all prostate cancers. Structurally, PSMA is a large extracellular carboxypeptidase domain that is tethered to the cellular membrane by a short transmembrane domain. Physiologically, PSMA is also expressed in normal tissue, including non-malignant prostate tissue, the kidney, the small intestine, and the central nervous system. In most tissues, PSMA likely contributes to folate uptake by cleaving the C-terminal glutamate from folic acid (Figure 1). Within the brain, PSMA regulates the level of N-acetylaspartylglutamate (NAAG) by catalyzing its degradation to glutamate. Structure of PSMA substrates and inhibitors. Left: structure of the PSMA substrate folic acid. The peptide bond (dashed box) linking the P1 glutamate residue (blue) to the remainder of the substrate (P1, red) is cleaved by PSMA. Right: Structure of the PSMA-PET agents 18F-DCFPyL and 68Ga-PSMA-11. The scissile peptide bond has been replaced by a non-hydrolyzable urea motif (red) to generate PMSA inhibitors. The P1 glutamate residue is essential for binding to PSMA, but a wide degree of variability is tolerated in the opposing end of the structure."
REF00605	PDC_02015	Prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Fatigue	1%	%	.	.	Phase 3	208 patients with prostate cancer.	.	.	8 h	.	.	8-10 mCi	PET/CT	"All patients were dosed with 9 mCi of 18F-DCFPyL and PET/CT images were obtained. 18F-DCFPyL avid lesions were detected in ~60% of the patients. To confirm the metastatic nature of these lesions, biopsies were obtained, if possible. If the lesion was not amendable to biopsy, validation is obtained by focused conventional follow-up imaging or biochemical response to external beam radiotherapy. The differentiation between the number of true metastases validated by other techniques (i.e. true positives, TP) and false positives (FP) allows for the calculation of the correct localization rate (CLR), where the CLR = TP/(TP + FP) * 100 (essentially, PPV with the added requirement of anatomic co-localization). Across all patients, the CLR ranged from 85% to 87% between readers, however the CLR improved as the baseline PSA increased, from 75% to 96% (PSA < 1.0 to PSA &ge; 5.0, respectively). The PPV of the 18F-DCFPyL PET/CT was found to vary by anatomic region and was highest for prostatic lesions (80%) and pelvic lymph nodes (71%), but lower for extrapelvic visceral/soft tissue masses (29%)."	"PSMA, also known as glutamate carboxypeptidase 2 or folate hydrolase 1, is highly expressed in nearly all prostate cancers. Structurally, PSMA is a large extracellular carboxypeptidase domain that is tethered to the cellular membrane by a short transmembrane domain. Physiologically, PSMA is also expressed in normal tissue, including non-malignant prostate tissue, the kidney, the small intestine, and the central nervous system. In most tissues, PSMA likely contributes to folate uptake by cleaving the C-terminal glutamate from folic acid (Figure 1). Within the brain, PSMA regulates the level of N-acetylaspartylglutamate (NAAG) by catalyzing its degradation to glutamate. Structure of PSMA substrates and inhibitors. Left: structure of the PSMA substrate folic acid. The peptide bond (dashed box) linking the P1 glutamate residue (blue) to the remainder of the substrate (P1, red) is cleaved by PSMA. Right: Structure of the PSMA-PET agents 18F-DCFPyL and 68Ga-PSMA-11. The scissile peptide bond has been replaced by a non-hydrolyzable urea motif (red) to generate PMSA inhibitors. The P1 glutamate residue is essential for binding to PSMA, but a wide degree of variability is tolerated in the opposing end of the structure."
REF00605	PDC_02015	Prostate cancer	.	Identified from the Human Clinical Data	High Expreesion	Hypertension	1%	%	.	.	Phase 3	208 patients with prostate cancer.	.	.	8 h	.	.	8-10 mCi	PET/CT	"All patients were dosed with 9 mCi of 18F-DCFPyL and PET/CT images were obtained. 18F-DCFPyL avid lesions were detected in ~60% of the patients. To confirm the metastatic nature of these lesions, biopsies were obtained, if possible. If the lesion was not amendable to biopsy, validation is obtained by focused conventional follow-up imaging or biochemical response to external beam radiotherapy. The differentiation between the number of true metastases validated by other techniques (i.e. true positives, TP) and false positives (FP) allows for the calculation of the correct localization rate (CLR), where the CLR = TP/(TP + FP) * 100 (essentially, PPV with the added requirement of anatomic co-localization). Across all patients, the CLR ranged from 85% to 87% between readers, however the CLR improved as the baseline PSA increased, from 75% to 96% (PSA < 1.0 to PSA &ge; 5.0, respectively). The PPV of the 18F-DCFPyL PET/CT was found to vary by anatomic region and was highest for prostatic lesions (80%) and pelvic lymph nodes (71%), but lower for extrapelvic visceral/soft tissue masses (29%)."	"PSMA, also known as glutamate carboxypeptidase 2 or folate hydrolase 1, is highly expressed in nearly all prostate cancers. Structurally, PSMA is a large extracellular carboxypeptidase domain that is tethered to the cellular membrane by a short transmembrane domain. Physiologically, PSMA is also expressed in normal tissue, including non-malignant prostate tissue, the kidney, the small intestine, and the central nervous system. In most tissues, PSMA likely contributes to folate uptake by cleaving the C-terminal glutamate from folic acid (Figure 1). Within the brain, PSMA regulates the level of N-acetylaspartylglutamate (NAAG) by catalyzing its degradation to glutamate. Structure of PSMA substrates and inhibitors. Left: structure of the PSMA substrate folic acid. The peptide bond (dashed box) linking the P1 glutamate residue (blue) to the remainder of the substrate (P1, red) is cleaved by PSMA. Right: Structure of the PSMA-PET agents 18F-DCFPyL and 68Ga-PSMA-11. The scissile peptide bond has been replaced by a non-hydrolyzable urea motif (red) to generate PMSA inhibitors. The P1 glutamate residue is essential for binding to PSMA, but a wide degree of variability is tolerated in the opposing end of the structure."
REF00599	PDC_02016	Rheumatoid arthritis	BALB/c male mice carrageenan-induced acute inflammation model.	Obtained from the Model Organism Data	.	Swelling inhibition value	41.00%	%	.	.	.	.	.	.	24.866 h	.	4 h	90.96 mg/kg	.	"To assess the anti-inflammatory efficacy of the conjugates, a carrageenan-induced acute inflammation model was developed in Balb/c male mice. Experimental mice were treated by injection of saline, free SIN, conjugate (L) or conjugate (C) in the tail vein at 1 h prior to the induction of paw edema. Photographs of the right hind paws indicated that swelling was milder in the mice treated with conjugate (C) and conjugate (L) than in the model group. Data for hind paw volumes suggested that conjugate (C) had the strongest therapeutic efficacy compared to that of the free drug SIN at 20.96 mg/kg and the model group. As previously reported, effective doses of SIN against experimental arthritis in vivo range from 15 mg/kg to 300 mg/kg body weight. Therefore, the dose of SIN was considered since the administration of 20.96 mg/kg is widely identified in the literature as a low dose for treating animals in arthritis mouse models without inducing side effects. The benefit of IV injections of conjugates at 90.96 mg/kg (eq. SIN) was clearly demonstrated by comparison with free SIN at the same molar dose. To verify the therapeutic efficacies of the conjugates, histological structures of paws were evaluated. Histological examination of the right hind paws revealed that the pedis skins contained massive lymphocyte, plasma cell and neutrophil infiltration in the paws of animals treated with saline. Animals treated with conjugates and free SIN showed less inflammatory cell infiltration, and conjugate (C) showed the mildest inflammation compared to the same dose of free SIN. To characterize the therapeutic efficacies of the conjugates more clearly, Image J software was used to statistically analyze the inflammatory cells in pathological sections (n = 7), and the results are shown in Fig. 6D. There were significant differences between the treatment groups and the model group (*p < 0.05, **p < 0.01, ***p < 0.001)."	"In this study, we utilized a synovial endothelium targeting peptide (CKSTHDRLC), which was identified and shown to preferentially locate at synovial xenografts in a human/SCID chimeric model of RA using ex vivo and in vivo screening of a phage peptide-display library. This peptide was subsequently developed as a targeting carrier for selective delivery of recombinant antibodies, cytokines, and nanoparticles. In this work, this target peptide was conjugated to SIN with a 6-aminocaproic acid linker to construct peptide-drug conjugates, and their characterization, stability, drugs released in vitro, therapeutic efficacy and in vivo bio-distribution are reported."
REF00599	PDC_02017	Rheumatoid arthritis	BALB/c male mice carrageenan-induced acute inflammation model.	Obtained from the Model Organism Data	.	Swelling inhibition value	58.30%	%	.	.	.	.	.	.	24.347 h	.	4 h	90.96 mg/kg	.	"To assess the anti-inflammatory efficacy of the conjugates, a carrageenan-induced acute inflammation model was developed in Balb/c male mice. Experimental mice were treated by injection of saline, free SIN, conjugate (L) or conjugate (C) in the tail vein at 1 h prior to the induction of paw edema. Photographs of the right hind paws indicated that swelling was milder in the mice treated with conjugate (C) and conjugate (L) than in the model group. Data for hind paw volumes suggested that conjugate (C) had the strongest therapeutic efficacy compared to that of the free drug SIN at 20.96 mg/kg and the model group. As previously reported, effective doses of SIN against experimental arthritis in vivo range from 15 mg/kg to 300 mg/kg body weight. Therefore, the dose of SIN was considered since the administration of 20.96 mg/kg is widely identified in the literature as a low dose for treating animals in arthritis mouse models without inducing side effects. The benefit of IV injections of conjugates at 90.96 mg/kg (eq. SIN) was clearly demonstrated by comparison with free SIN at the same molar dose. To verify the therapeutic efficacies of the conjugates, histological structures of paws were evaluated. Histological examination of the right hind paws revealed that the pedis skins contained massive lymphocyte, plasma cell and neutrophil infiltration in the paws of animals treated with saline. Animals treated with conjugates and free SIN showed less inflammatory cell infiltration, and conjugate (C) showed the mildest inflammation compared to the same dose of free SIN. To characterize the therapeutic efficacies of the conjugates more clearly, Image J software was used to statistically analyze the inflammatory cells in pathological sections (n = 7), and the results are shown in Fig. 6D. There were significant differences between the treatment groups and the model group (*p < 0.05, **p < 0.01, ***p < 0.001)."	"In this study, we utilized a synovial endothelium targeting peptide (CKSTHDRLC), which was identified and shown to preferentially locate at synovial xenografts in a human/SCID chimeric model of RA using ex vivo and in vivo screening of a phage peptide-display library. This peptide was subsequently developed as a targeting carrier for selective delivery of recombinant antibodies, cytokines, and nanoparticles. In this work, this target peptide was conjugated to SIN with a 6-aminocaproic acid linker to construct peptide-drug conjugates, and their characterization, stability, drugs released in vitro, therapeutic efficacy and in vivo bio-distribution are reported."
REF00598	PDC_02018	Pancreatic cancer	BxPC-3 cells (KRAS wild type) xenografted mice.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	12.50%	%	.	.	.	.	Pancreatic ductal adenocarcinoma	BxPC-3 cell	8.51 &plusmn; 0.50 h	.	30 days	10 mg/kg	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Pancreatic cancer	MIA PaCa-2 cells (G12C KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	99.90%	%	.	.	.	.	Pancreatic ductal adenocarcinoma	MIA PaCa-2 (KRAS G12C) cell	8.51 &plusmn; 0.50 h	.	30 days	5 mg/kg	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Pancreatic cancer	AsPC-1 cells (G12D KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	69.10%	%	.	.	.	.	Pancreatic ductal adenocarcinoma	AsPC-1 (KRAS G12D) cell	8.51 &plusmn; 0.50 h	.	30 days	5 mg/kg	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Colon cancer	HCT116 cells (G13D KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	86.80%	%	.	.	.	.	Colon carcinoma	HCT 116 (KRAS G13D) cell	8.51 &plusmn; 0.50 h	.	30 days	5 mg/kg	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Lung cancer	A549 cells (G12S KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	80.00%	%	.	.	.	.	Lung adenocarcinoma	A-549 (KRAS G12S) cell	8.51 &plusmn; 0.50 h	.	30 days	5 mg/kg	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Breast cancer	MDA-MB-231 cells (G13D KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	96.50%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 (KRAS G13D) cell	8.51 &plusmn; 0.50 h	.	30 days	5 mg/kg	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Pancreatic cancer	MIA PaCa-2 cells (G12C KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	100.00%	%	.	.	.	.	Pancreatic ductal adenocarcinoma	MIA PaCa-2 (KRAS G12C) cell	8.51 &plusmn; 0.50 h	.	30 days	10 mg/kg	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Pancreatic cancer	AsPC-1 cells (G12D KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	95.10%	%	.	.	.	.	Pancreatic ductal adenocarcinoma	AsPC-1 (KRAS G12D) cell	8.51 &plusmn; 0.50 h	.	30 days	10 mg/kg	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Colon cancer	HCT116 cells (G13D KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	97.80%	%	.	.	.	.	Colon carcinoma	HCT 116 (KRAS G13D) cell	8.51 &plusmn; 0.50 h	.	30 days	10 mg/kg	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Lung cancer	A549 cells (G12S KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	95.10%	%	.	.	.	.	Lung adenocarcinoma	A-549 (KRAS G12S) cell	8.51 &plusmn; 0.50 h	.	30 days	10 mg/kg	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Breast cancer	MDA-MB-231 cells (G13D KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	100.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 (KRAS G13D) cell	8.51 &plusmn; 0.50 h	.	30 days	10 mg/kg	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Pancreatic cancer	MIA PaCa-2 cells (G12C KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Albumin uptake rate	68.43%	%	.	.	.	.	Pancreatic ductal adenocarcinoma	MIA PaCa-2 (KRAS G12C) cell	8.51 &plusmn; 0.50 h	.	.	.	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Pancreatic cancer	AsPC-1 cells (G12D KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Albumin uptake rate	6.67%	%	.	.	.	.	Pancreatic ductal adenocarcinoma	AsPC-1 (KRAS G12D) cell	8.51 &plusmn; 0.50 h	.	.	.	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Colon cancer	HCT116 cells (G13D KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Albumin uptake rate	52.30%	%	.	.	.	.	Colon carcinoma	HCT 116 (KRAS G13D) cell	8.51 &plusmn; 0.50 h	.	.	.	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Lung cancer	A549 cells (G12S KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Albumin uptake rate	12.80%	%	.	.	.	.	Lung adenocarcinoma	A-549 (KRAS G12S) cell	8.51 &plusmn; 0.50 h	.	.	.	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00598	PDC_02018	Breast cancer	MDA-MB-231 cells (G13D KRAS mutation) xenografted mice model.	Discovered Using Cell Line-derived Xenograft Model	.	Albumin uptake rate	51.57%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 (KRAS G13D) cell	8.51 &plusmn; 0.50 h	.	.	.	.	"The in vivo anti-cancer activity of MPD1 was evaluated in MIA PaCa-2- and BxPC-3-xenografted mice. When the average tumor volume reached 200 mm<sup>3</sup>, mice were treated with 5 or 10 mg/kg of MPD1 via intravenous administration every other day for 4 weeks. MPD1 demonstrated potent anti-cancer activity, yielding 100% and 113% TGI for 5 and 10 mg/kg, respectively, compared to the control group in MIA PaCa-2 tumor model (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 268.48 &plusmn; 135.66, P < 0.0001; 10 mg/kg, 46.19 &plusmn; 45.92, P < 0.0001). However, when BxPC-3-xenografted mice were treated with the same doses of MPD1, no therapeutic efficacy was observed (30-day tumor volume [mm<sup>3</sup>]: 5 mg/kg, 1728.68 &plusmn; 311.91, P = 0.77; 10 mg/kg, 1221.27 &plusmn; 306.77, P = 0.36). There were no noticeable body weight changes or obvious abnormalities in heart, kidney, liver, and spleen in histological assessment indicating that MPD1 was tolerable up to 10 mg/kg when administered 14 times in both xenograft models. Immunohistochemical analysis of the caspase-3 expression and TUNEL staining of MIA PaCa-2 and BxPC-3 tumors from MPD1-treated mice confirmed that MPD1 caused a substantial degree of apoptosis and caspase-3 upregulation only in MIA PaCa-2. In contrast, an increased dose of 10 mg/kg of MPD1 did not show upregulated apoptotic events or caspase-3 expression in BxPC-3 tumors."	"To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner."
REF00597	PDC_02019	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal effective concentration (EC50)	4.2 &plusmn;0.6 nM	nM	.	.	.	.	Digestive system neoplasms	AR42J (SSTR2+) cell	.	.	72 h	.	MTS assay	"With bioconjugates 5-7 in hand, we evaluated their cytotoxicity by assaying cell viability on an sstr2-positive rat pancreatic cancer Ar42J cells, using free amatoxins as controls. The MTS cell viability assay showed that all three PDCs were effective at reducing the viability of Ar42J cells in the low nM range, providing calculated EC50 values of 4.2, and 2.3 nM for conjugates 6 and 7, respectively; these displayed up to 1000-fold enhancement in apparent cytotoxicity compared to free amatoxins 3 and 4, both of which gave calculated EC50 values of &tide;2 &mu;M. This points to successful targeting and intracellular accumulation of toxin inside cells through an sstr2-mediated uptake inside the cells. Further evidence supporting target-mediated uptake is the micromolar toxicity of bioconjugates to the sstr2-negative CHO cell line that is otherwise sensitive to non-targeted amanitin. In comparison to -amanitin and synthetic amatoxins 3 and 4, bioconjugates 5-7 are 7- to 14-fold less toxic to CHO cells (control cell line), likely owing to impaired uptake of octreotate-amanitin conjugates that must enter via diffusion mediated processes or other non-specific import mechanisms that are currently unknown. In addition, a blocking study was run in the presence of free TATE-N32, which led to the expected reduction in apparent toxicity."	"Towards these ends, we report on the design of a modular and user-friendly approach to enable bio-orthogonal conjugation of synthetic amanitins to three different linkers that are elaborated to three potent peptide-amanitin conjugates that differ by their mode of toxin release, as defined by the linker. Octreotate (TATE-N3, 2) was chosen as it is a circulation-stable octapeptide somatostatin analog that agonizes somatostatin receptors (Kd &tide; 0.4 nM for sstr2). Targeting sstr2 has been successfully exploited for drug delivery, cancer imaging, and radiotherapy owing to the high levels of sstr2 expression on neuroendocrine tumors (e.g. carcinoids, pancreatic islet cell tumors, thyroid carcinomas, and small lung cancer to name a few). While this is the first report of an octreotate-amanitin conjugate, herein, octreotate serves as an exemplar to highlight the potential for developing peptide-amanitin conjugates in targeted applications."
REF00597	PDC_02020	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal effective concentration (EC50)	2.3 &plusmn;0.8 nM	nM	.	.	.	.	Digestive system neoplasms	AR42J (SSTR2+) cell	.	.	72 h	.	MTS assay	"With bioconjugates 5-7 in hand, we evaluated their cytotoxicity by assaying cell viability on an sstr2-positive rat pancreatic cancer Ar42J cells, using free amatoxins as controls. The MTS cell viability assay showed that all three PDCs were effective at reducing the viability of Ar42J cells in the low nM range, providing calculated EC50 values of 4.2, and 2.3 nM for conjugates 6 and 7, respectively; these displayed up to 1000-fold enhancement in apparent cytotoxicity compared to free amatoxins 3 and 4, both of which gave calculated EC50 values of &tide;2 &mu;M. This points to successful targeting and intracellular accumulation of toxin inside cells through an sstr2-mediated uptake inside the cells. Further evidence supporting target-mediated uptake is the micromolar toxicity of bioconjugates to the sstr2-negative CHO cell line that is otherwise sensitive to non-targeted amanitin. In comparison to -amanitin and synthetic amatoxins 3 and 4, bioconjugates 5-7 are 7- to 14-fold less toxic to CHO cells (control cell line), likely owing to impaired uptake of octreotate-amanitin conjugates that must enter via diffusion mediated processes or other non-specific import mechanisms that are currently unknown. In addition, a blocking study was run in the presence of free TATE-N32, which led to the expected reduction in apparent toxicity."	"Towards these ends, we report on the design of a modular and user-friendly approach to enable bio-orthogonal conjugation of synthetic amanitins to three different linkers that are elaborated to three potent peptide-amanitin conjugates that differ by their mode of toxin release, as defined by the linker. Octreotate (TATE-N3, 2) was chosen as it is a circulation-stable octapeptide somatostatin analog that agonizes somatostatin receptors (Kd &tide; 0.4 nM for sstr2). Targeting sstr2 has been successfully exploited for drug delivery, cancer imaging, and radiotherapy owing to the high levels of sstr2 expression on neuroendocrine tumors (e.g. carcinoids, pancreatic islet cell tumors, thyroid carcinomas, and small lung cancer to name a few). While this is the first report of an octreotate-amanitin conjugate, herein, octreotate serves as an exemplar to highlight the potential for developing peptide-amanitin conjugates in targeted applications."
REF00597	PDC_02019	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	5.0 &plusmn;0.6 &mu;M	&mu;M	.	.	.	.	Digestive system neoplasms	AR42J (SSTR2+) cell	.	.	72 h	.	MTS assay	"With bioconjugates 5-7 in hand, we evaluated their cytotoxicity by assaying cell viability on an sstr2-positive rat pancreatic cancer Ar42J cells, using free amatoxins as controls. The MTS cell viability assay showed that all three PDCs were effective at reducing the viability of Ar42J cells in the low nM range, providing calculated EC50 values of 4.2, and 2.3 nM for conjugates 6 and 7, respectively; these displayed up to 1000-fold enhancement in apparent cytotoxicity compared to free amatoxins 3 and 4, both of which gave calculated EC50 values of &tide;2 &mu;M. This points to successful targeting and intracellular accumulation of toxin inside cells through an sstr2-mediated uptake inside the cells. Further evidence supporting target-mediated uptake is the micromolar toxicity of bioconjugates to the sstr2-negative CHO cell line that is otherwise sensitive to non-targeted amanitin. In comparison to -amanitin and synthetic amatoxins 3 and 4, bioconjugates 5-7 are 7- to 14-fold less toxic to CHO cells (control cell line), likely owing to impaired uptake of octreotate-amanitin conjugates that must enter via diffusion mediated processes or other non-specific import mechanisms that are currently unknown. In addition, a blocking study was run in the presence of free TATE-N32, which led to the expected reduction in apparent toxicity."	"Towards these ends, we report on the design of a modular and user-friendly approach to enable bio-orthogonal conjugation of synthetic amanitins to three different linkers that are elaborated to three potent peptide-amanitin conjugates that differ by their mode of toxin release, as defined by the linker. Octreotate (TATE-N3, 2) was chosen as it is a circulation-stable octapeptide somatostatin analog that agonizes somatostatin receptors (Kd &tide; 0.4 nM for sstr2). Targeting sstr2 has been successfully exploited for drug delivery, cancer imaging, and radiotherapy owing to the high levels of sstr2 expression on neuroendocrine tumors (e.g. carcinoids, pancreatic islet cell tumors, thyroid carcinomas, and small lung cancer to name a few). While this is the first report of an octreotate-amanitin conjugate, herein, octreotate serves as an exemplar to highlight the potential for developing peptide-amanitin conjugates in targeted applications."
REF00597	PDC_02020	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	8.7 &plusmn; 0.5 &mu;M	&mu;M	.	.	.	.	Digestive system neoplasms	AR42J (SSTR2+) cell	.	.	72 h	.	MTS assay	"With bioconjugates 5-7 in hand, we evaluated their cytotoxicity by assaying cell viability on an sstr2-positive rat pancreatic cancer Ar42J cells, using free amatoxins as controls. The MTS cell viability assay showed that all three PDCs were effective at reducing the viability of Ar42J cells in the low nM range, providing calculated EC50 values of 4.2, and 2.3 nM for conjugates 6 and 7, respectively; these displayed up to 1000-fold enhancement in apparent cytotoxicity compared to free amatoxins 3 and 4, both of which gave calculated EC50 values of &tide;2 &mu;M. This points to successful targeting and intracellular accumulation of toxin inside cells through an sstr2-mediated uptake inside the cells. Further evidence supporting target-mediated uptake is the micromolar toxicity of bioconjugates to the sstr2-negative CHO cell line that is otherwise sensitive to non-targeted amanitin. In comparison to -amanitin and synthetic amatoxins 3 and 4, bioconjugates 5-7 are 7- to 14-fold less toxic to CHO cells (control cell line), likely owing to impaired uptake of octreotate-amanitin conjugates that must enter via diffusion mediated processes or other non-specific import mechanisms that are currently unknown. In addition, a blocking study was run in the presence of free TATE-N32, which led to the expected reduction in apparent toxicity."	"Towards these ends, we report on the design of a modular and user-friendly approach to enable bio-orthogonal conjugation of synthetic amanitins to three different linkers that are elaborated to three potent peptide-amanitin conjugates that differ by their mode of toxin release, as defined by the linker. Octreotate (TATE-N3, 2) was chosen as it is a circulation-stable octapeptide somatostatin analog that agonizes somatostatin receptors (Kd &tide; 0.4 nM for sstr2). Targeting sstr2 has been successfully exploited for drug delivery, cancer imaging, and radiotherapy owing to the high levels of sstr2 expression on neuroendocrine tumors (e.g. carcinoids, pancreatic islet cell tumors, thyroid carcinomas, and small lung cancer to name a few). While this is the first report of an octreotate-amanitin conjugate, herein, octreotate serves as an exemplar to highlight the potential for developing peptide-amanitin conjugates in targeted applications."
REF00597	PDC_02021	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10 &mu;M	&mu;M	.	.	.	.	Digestive system neoplasms	AR42J (SSTR2+) cell	.	.	72 h	.	MTS assay	"With bioconjugates 5-7 in hand, we evaluated their cytotoxicity by assaying cell viability on an sstr2-positive rat pancreatic cancer Ar42J cells, using free amatoxins as controls. The MTS cell viability assay showed that all three PDCs were effective at reducing the viability of Ar42J cells in the low nM range, providing calculated EC50 values of 4.2, and 2.3 nM for conjugates 6 and 7, respectively; these displayed up to 1000-fold enhancement in apparent cytotoxicity compared to free amatoxins 3 and 4, both of which gave calculated EC50 values of &tide;2 &mu;M. This points to successful targeting and intracellular accumulation of toxin inside cells through an sstr2-mediated uptake inside the cells. Further evidence supporting target-mediated uptake is the micromolar toxicity of bioconjugates to the sstr2-negative CHO cell line that is otherwise sensitive to non-targeted amanitin. In comparison to -amanitin and synthetic amatoxins 3 and 4, bioconjugates 5-7 are 7- to 14-fold less toxic to CHO cells (control cell line), likely owing to impaired uptake of octreotate-amanitin conjugates that must enter via diffusion mediated processes or other non-specific import mechanisms that are currently unknown. In addition, a blocking study was run in the presence of free TATE-N32, which led to the expected reduction in apparent toxicity."	"Towards these ends, we report on the design of a modular and user-friendly approach to enable bio-orthogonal conjugation of synthetic amanitins to three different linkers that are elaborated to three potent peptide-amanitin conjugates that differ by their mode of toxin release, as defined by the linker. Octreotate (TATE-N3, 2) was chosen as it is a circulation-stable octapeptide somatostatin analog that agonizes somatostatin receptors (Kd &tide; 0.4 nM for sstr2). Targeting sstr2 has been successfully exploited for drug delivery, cancer imaging, and radiotherapy owing to the high levels of sstr2 expression on neuroendocrine tumors (e.g. carcinoids, pancreatic islet cell tumors, thyroid carcinomas, and small lung cancer to name a few). While this is the first report of an octreotate-amanitin conjugate, herein, octreotate serves as an exemplar to highlight the potential for developing peptide-amanitin conjugates in targeted applications."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 haematological treatment-emergent adverse event	8%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 neutropenia	6%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 anaemia	24%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 thrombocytopenia	7%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 neutrophil count decreased	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 platelet count decreased	3%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 leukopenia	4%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 white blood cell count decreased	4%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 lymphopenia	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 pancytopenia	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 haematological treatment-emergent adverse event	33%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 neutropenia	28%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 anaemia	40%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 thrombocytopenia	32%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 neutrophil count decreased	8%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 platelet count decreased	8%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 leukopenia	6%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 white blood cell count decreased	3%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 lymphopenia	2%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 pancytopenia	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 haematological treatment-emergent adverse event	53%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 neutropenia	26%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 anaemia	2%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 thrombocytopenia	31%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 neutrophil count decreased	4%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 platelet count decreased	7%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 leukopenia	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 white blood cell count decreased	3%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 lymphopenia	2%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 pancytopenia	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 haematological treatment-emergent adverse event	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 neutropenia	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 pancytopenia	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 non-haematological treatment-emergent adverse event	44%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 fatigue	14%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 asthenia	12%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 pyrexia	13%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 nausea	13%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 diarrhoea	12%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 upper respiratory tract infection	11%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 pneumonia	3%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 constipation	7%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 bronchitis	4%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 covid-19 pneumonia	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 urinary tract infection	4%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 lower respiratory tract infection	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 pulmonary embolism	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 renal failure	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 respiratory failure	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 general physical health deterioration	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 abdominal mass	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 multiple organ dysfunction syndrome	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 sepsis	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 brain oedema	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 cardiac arrest	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 cardiac failure acute	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 cerebral haemorrhage	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 escherichia sepsis	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 myelodysplastic syndromes	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 oesophageal carcinoma	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 pleural effusion	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 post-procedural complication	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 pulmonary oedema	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 subdural haematoma	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 sudden cardiac death	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 septic shock	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 cerebrovascular insufficiency	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 craniocerebral injury	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 death for unknown reason	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 respiratory arrest	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 1-2 sudden death	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 non-haematological treatment-emergent adverse event	32%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 fatigue	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 asthenia	2%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 pyrexia	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 nausea	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 diarrhoea	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 upper respiratory tract infection	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 pneumonia	4%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 constipation	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 bronchitis	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 covid-19 pneumonia	2%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 urinary tract infection	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 lower respiratory tract infection	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 pulmonary embolism	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 renal failure	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 respiratory failure	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 general physical health deterioration	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 abdominal mass	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 multiple organ dysfunction syndrome	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 sepsis	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 brain oedema	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 cardiac arrest	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 cardiac failure acute	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 cerebral haemorrhage	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 escherichia sepsis	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 myelodysplastic syndromes	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 oesophageal carcinoma	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 pleural effusion	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 post-procedural complication	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 pulmonary oedema	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 subdural haematoma	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 sudden cardiac death	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 septic shock	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 cerebrovascular insufficiency	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 craniocerebral injury	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 death for unknown reason	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 respiratory arrest	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3 sudden death	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 non-haematological treatment-emergent adverse event	2%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 fatigue	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 asthenia	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 pyrexia	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 nausea	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 diarrhoea	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 upper respiratory tract infection	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 pneumonia	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 constipation	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 bronchitis	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 covid-19 pneumonia	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 urinary tract infection	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 lower respiratory tract infection	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 pulmonary embolism	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 renal failure	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 respiratory failure	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 general physical health deterioration	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 abdominal mass	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 multiple organ dysfunction syndrome	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 sepsis	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 brain oedema	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 cardiac arrest	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 cardiac failure acute	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 cerebral haemorrhage	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 escherichia sepsis	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 myelodysplastic syndromes	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 oesophageal carcinoma	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 pleural effusion	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 post-procedural complication	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 pulmonary oedema	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 subdural haematoma	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 sudden cardiac death	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 septic shock	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 cerebrovascular insufficiency	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 craniocerebral injury	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 death for unknown reason	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 respiratory arrest	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 sudden death	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 non-haematological treatment-emergent adverse event	11%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 fatigue	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 asthenia	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 pyrexia	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 nausea	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 diarrhoea	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 upper respiratory tract infection	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 pneumonia	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 constipation	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 bronchitis	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 covid-19 pneumonia	3%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 urinary tract infection	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 lower respiratory tract infection	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 pulmonary embolism	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 renal failure	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 respiratory failure	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 general physical health deterioration	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 abdominal mass	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 multiple organ dysfunction syndrome	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 sepsis	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 brain oedema	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 cardiac arrest	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 cardiac failure acute	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 cerebral haemorrhage	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 escherichia sepsis	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 myelodysplastic syndromes	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 oesophageal carcinoma	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 pleural effusion	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 post-procedural complication	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 pulmonary oedema	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 subdural haematoma	1%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 sudden cardiac death	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 septic shock	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 cerebrovascular insufficiency	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 craniocerebral injury	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 death for unknown reason	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 respiratory arrest	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 5 sudden death	0%	%	.	.	.	228 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	33.00%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Clinical benefit rate	50%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	0%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	3%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	9%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	20%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Minimal response rate	17%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	28%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Progressive disease (PD)	15%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	32.00%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Clinical benefit rate	47%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	1%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Complete response (CR)	2%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	10%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Partial response (PR)	19%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Minimal response rate	15%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Stable disease (SD)	24%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00596	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Progressive disease (PD)	19%	%	.	.	.	246 patients with multiple myeloma refractory to lenalidomide.	.	.	.	.	.	40 mg	.	"In the safety population, the median duration of treatment was 58 months (IQR 28-111) in the melflufen group and 51 months (26-92) in the pomalidomide group. Patients received a median of five treatment cycles in each treatment group (melflufen: IQR 3-11; pomalidomide: IQR 3-10). The most common treatment-emergent adverse events by preferred term and treatment group are summarised in table 2 and the appendix (pp 23-31 ), and disaggregated by sex in the appendix (pp 32-35 ). The most common haematological grade 3 or 4 events in the melflufen and pomalidomide groups were neutropenia (123 [54%] of 228 vs 102 [41%] of 246), thrombocytopenia (143 [63%] vs 26 [11%]), and anaemia (97 [43%] vs 44 [18%]), and the most common grade 3 or 4 non-haematological event was pneumonia (ten [4%] vs 20 [8%]). The most common grade 3 or 4 treatment-related treatment-emergent adverse events in the melflufen and pomalidomide groups were thrombocytopenia (138 [61%] vs 22 [9%]), neutropenia (122 [54%] vs 97 [39%]), anaemia (87 [38%] vs 25 [10%] ). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) patients in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]), and were considered to be treatment related in 42 (18%) in the melflufen group and 52 (21%) in the pomalidomide group. In the safety population, 106 (46%) patients in the melflufen group and 106 (43%) patients in the pomalidomide group died overall. 23 (10%) patients in the melflufen group and 33 (13%) in the pomalidomide group died within 30 days of receiving their last dose of study drug; 83 (36%) in the melflufen group and 73 (30%), in the pomalidomide group died 30 days after having received their last dose of study medication. Additionally, 13 patients who were randomly assigned but not treated died (assigned to melflufen group, 11 [61%] of 18; pomalidomide group, two [67%] of three). In an exploratory analysis of prespecified subgroups of clinical relevance in the ITT population, progression-free survival data favoured melflufen in most subgroups, including patients aged 75 years and older (HR 043 [95% CI 024-076]; p=00031) and patients without a previous autologous HSCT (HR 059 [044-079]; p=00004). By contrast, overall survival data favoured pomalidomide in patients younger than 65 years (HR 171 [95% CI 109-269]; p=0019) and those with a previous autologous HSCT (HR 161 [109-240]; p=0017). Age and previous autologous HSCT remained significant prognostic factors on the basis of an interaction test."	"Melphalan flufenamide (known as melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumour cells. Due to its high lipophilicity and affinity for aminopeptidases, melflufen can passively enter tumour cells and release cytotoxic, hydrophilic alkylating agents (melphalan and desethyl-melflufen) that remain trapped within cells. Melflufen uses a novel approach, whereby increased aminopeptidase activity is used to achieve selective release of alkylating agents inside tumour cells."
REF00595	PDC_02022	SARS-CoV infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	8.63 &plusmn; 0.55 &mu;M	&mu;M	.	.	.	.	COVID-19	SARS-CoV-2	.	.	.	.	.	"The enzymatic activities of SARS-CoV-2 PLpro were tested using the fluorogenic peptide substrate LRGG-AMC. The sulfonium-tethered peptides without GRL0617 could not efficiently inhibit SARS-CoV-2 PLpro, while the sulfonium-tethered peptide conjugate GRL0617 has a better inhibition ability. Specifically, IC50 values of EM-C and EC-M were 7.40 &plusmn; 0.37 and 8.63 &plusmn; 0.55 &mu;M, respectively. Enzymatic activities of PLpro were inhibited by different PDCs or GRL0617. (A) Enzymatic activity of SARS-CoV-2 PLpro was inhibited by different PDCs or GRL0617. The activity assay was performed using the peptide LRGG-ACC as a substrate. Error bars represent standard errors of mean of at least three independent measurements. (B) IC50 of different PDCs or GRL0617 in SARS-CoV-2 PLpro. IC50 of EM-C was 7.40 &plusmn; 0.37 &mu;M. IC50 of EC-M was 8.63 &plusmn; 0.55 &mu;M. IC50 of ELRGG was 15.38 &plusmn; 1.63 &mu;M. IC50 of GRL0617 was 2.64 &plusmn; 0.34 &mu;M. (C) Enzymatic activity of SARS-CoV PLpro was inhibited by different PDCs or GRL0617. (D) Enzyme activity of MERS PLpro was inhibited by different PDCs or GRL0617. Also, we tested the peptide inhibition ability to SARS-CoV PLpro and MERS PLpro. There is a high sequence identity (83%) between the SARS-CoV-2 PLpro and SARS-CoV PLpro. The IC50 value of EM-C against SARS-CoV PLpro was 3.43 &plusmn; 0.54 &mu;M, close to GRL0617 (IC50 = 2.60 &plusmn; 0.05 &mu;M). Its linear analogue showed weaker inhibition. The GRL0617, EC-M, EM-C, and ELRGG could not inhibit MERS PLpro. Both EM-C and EC-M showed better inhibition for SARS-CoV PLpro than SARS-CoV-2 PLpro."	"Peptide-drug conjugates (PDCs) are a class of novel molecules widely designed and synthesized for delivering drug payloads. In this work, we designed a novel PDC in which the GRL0617 was linked to the sulfonium-tethered peptides derived from PLpro-specific substrate LRGG. This conjugate could covalently label PLpro active site C111. Two conjugates EM-C and EC-M showed a promising in vitro IC50 of 7.40 &plusmn; 0.37 and 8.63 &plusmn; 0.55 &mu;M, respectively. Both conjugates could effectively inhibit anti-ISGylation activities of PLpro in cells, and there is low toxicity of PDC EC-M and EM-C in different cells."
REF00595	PDC_02023	SARS-CoV infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	7.40&plusmn;0.37 &mu;M	&mu;M	.	.	.	.	COVID-19	SARS-CoV-2	.	.	.	.	.	"The enzymatic activities of SARS-CoV-2 PLpro were tested using the fluorogenic peptide substrate LRGG-AMC. The sulfonium-tethered peptides without GRL0617 could not efficiently inhibit SARS-CoV-2 PLpro, while the sulfonium-tethered peptide conjugate GRL0617 has a better inhibition ability. Specifically, IC50 values of EM-C and EC-M were 7.40 &plusmn; 0.37 and 8.63 &plusmn; 0.55 &mu;M, respectively. Enzymatic activities of PLpro were inhibited by different PDCs or GRL0617. (A) Enzymatic activity of SARS-CoV-2 PLpro was inhibited by different PDCs or GRL0617. The activity assay was performed using the peptide LRGG-ACC as a substrate. Error bars represent standard errors of mean of at least three independent measurements. (B) IC50 of different PDCs or GRL0617 in SARS-CoV-2 PLpro. IC50 of EM-C was 7.40 &plusmn; 0.37 &mu;M. IC50 of EC-M was 8.63 &plusmn; 0.55 &mu;M. IC50 of ELRGG was 15.38 &plusmn; 1.63 &mu;M. IC50 of GRL0617 was 2.64 &plusmn; 0.34 &mu;M. (C) Enzymatic activity of SARS-CoV PLpro was inhibited by different PDCs or GRL0617. (D) Enzyme activity of MERS PLpro was inhibited by different PDCs or GRL0617. Also, we tested the peptide inhibition ability to SARS-CoV PLpro and MERS PLpro. There is a high sequence identity (83%) between the SARS-CoV-2 PLpro and SARS-CoV PLpro. The IC50 value of EM-C against SARS-CoV PLpro was 3.43 &plusmn; 0.54 &mu;M, close to GRL0617 (IC50 = 2.60 &plusmn; 0.05 &mu;M). Its linear analogue showed weaker inhibition. The GRL0617, EC-M, EM-C, and ELRGG could not inhibit MERS PLpro. Both EM-C and EC-M showed better inhibition for SARS-CoV PLpro than SARS-CoV-2 PLpro."	"Peptide-drug conjugates (PDCs) are a class of novel molecules widely designed and synthesized for delivering drug payloads. In this work, we designed a novel PDC in which the GRL0617 was linked to the sulfonium-tethered peptides derived from PLpro-specific substrate LRGG. This conjugate could covalently label PLpro active site C111. Two conjugates EM-C and EC-M showed a promising in vitro IC50 of 7.40 &plusmn; 0.37 and 8.63 &plusmn; 0.55 &mu;M, respectively. Both conjugates could effectively inhibit anti-ISGylation activities of PLpro in cells, and there is low toxicity of PDC EC-M and EM-C in different cells."
REF00595	PDC_02024	SARS-CoV infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	15.38&plusmn;1.63 &mu;M	&mu;M	.	.	.	.	COVID-19	SARS-CoV-2	.	.	.	.	.	"The enzymatic activities of SARS-CoV-2 PLpro were tested using the fluorogenic peptide substrate LRGG-AMC. The sulfonium-tethered peptides without GRL0617 could not efficiently inhibit SARS-CoV-2 PLpro, while the sulfonium-tethered peptide conjugate GRL0617 has a better inhibition ability. Specifically, IC50 values of EM-C and EC-M were 7.40 &plusmn; 0.37 and 8.63 &plusmn; 0.55 &mu;M, respectively. Enzymatic activities of PLpro were inhibited by different PDCs or GRL0617. (A) Enzymatic activity of SARS-CoV-2 PLpro was inhibited by different PDCs or GRL0617. The activity assay was performed using the peptide LRGG-ACC as a substrate. Error bars represent standard errors of mean of at least three independent measurements. (B) IC50 of different PDCs or GRL0617 in SARS-CoV-2 PLpro. IC50 of EM-C was 7.40 &plusmn; 0.37 &mu;M. IC50 of EC-M was 8.63 &plusmn; 0.55 &mu;M. IC50 of ELRGG was 15.38 &plusmn; 1.63 &mu;M. IC50 of GRL0617 was 2.64 &plusmn; 0.34 &mu;M. (C) Enzymatic activity of SARS-CoV PLpro was inhibited by different PDCs or GRL0617. (D) Enzyme activity of MERS PLpro was inhibited by different PDCs or GRL0617. Also, we tested the peptide inhibition ability to SARS-CoV PLpro and MERS PLpro. There is a high sequence identity (83%) between the SARS-CoV-2 PLpro and SARS-CoV PLpro. The IC50 value of EM-C against SARS-CoV PLpro was 3.43 &plusmn; 0.54 &mu;M, close to GRL0617 (IC50 = 2.60 &plusmn; 0.05 &mu;M). Its linear analogue showed weaker inhibition. The GRL0617, EC-M, EM-C, and ELRGG could not inhibit MERS PLpro. Both EM-C and EC-M showed better inhibition for SARS-CoV PLpro than SARS-CoV-2 PLpro."	"Peptide-drug conjugates (PDCs) are a class of novel molecules widely designed and synthesized for delivering drug payloads. In this work, we designed a novel PDC in which the GRL0617 was linked to the sulfonium-tethered peptides derived from PLpro-specific substrate LRGG. This conjugate could covalently label PLpro active site C111. Two conjugates EM-C and EC-M showed a promising in vitro IC50 of 7.40 &plusmn; 0.37 and 8.63 &plusmn; 0.55 &mu;M, respectively. Both conjugates could effectively inhibit anti-ISGylation activities of PLpro in cells, and there is low toxicity of PDC EC-M and EM-C in different cells."
REF00595	PDC_02022	SARS-CoV infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	16.38&plusmn;0.81 &mu;M	&mu;M	.	.	.	.	COVID-19	SARS-CoV-2	.	.	.	.	.	"The enzymatic activities of SARS-CoV-2 PLpro were tested using the fluorogenic peptide substrate LRGG-AMC. The sulfonium-tethered peptides without GRL0617 could not efficiently inhibit SARS-CoV-2 PLpro, while the sulfonium-tethered peptide conjugate GRL0617 has a better inhibition ability. Specifically, IC50 values of EM-C and EC-M were 7.40 &plusmn; 0.37 and 8.63 &plusmn; 0.55 &mu;M, respectively. Enzymatic activities of PLpro were inhibited by different PDCs or GRL0617. (A) Enzymatic activity of SARS-CoV-2 PLpro was inhibited by different PDCs or GRL0617. The activity assay was performed using the peptide LRGG-ACC as a substrate. Error bars represent standard errors of mean of at least three independent measurements. (B) IC50 of different PDCs or GRL0617 in SARS-CoV-2 PLpro. IC50 of EM-C was 7.40 &plusmn; 0.37 &mu;M. IC50 of EC-M was 8.63 &plusmn; 0.55 &mu;M. IC50 of ELRGG was 15.38 &plusmn; 1.63 &mu;M. IC50 of GRL0617 was 2.64 &plusmn; 0.34 &mu;M. (C) Enzymatic activity of SARS-CoV PLpro was inhibited by different PDCs or GRL0617. (D) Enzyme activity of MERS PLpro was inhibited by different PDCs or GRL0617. Also, we tested the peptide inhibition ability to SARS-CoV PLpro and MERS PLpro. There is a high sequence identity (83%) between the SARS-CoV-2 PLpro and SARS-CoV PLpro. The IC50 value of EM-C against SARS-CoV PLpro was 3.43 &plusmn; 0.54 &mu;M, close to GRL0617 (IC50 = 2.60 &plusmn; 0.05 &mu;M). Its linear analogue showed weaker inhibition. The GRL0617, EC-M, EM-C, and ELRGG could not inhibit MERS PLpro. Both EM-C and EC-M showed better inhibition for SARS-CoV PLpro than SARS-CoV-2 PLpro."	"Peptide-drug conjugates (PDCs) are a class of novel molecules widely designed and synthesized for delivering drug payloads. In this work, we designed a novel PDC in which the GRL0617 was linked to the sulfonium-tethered peptides derived from PLpro-specific substrate LRGG. This conjugate could covalently label PLpro active site C111. Two conjugates EM-C and EC-M showed a promising in vitro IC50 of 7.40 &plusmn; 0.37 and 8.63 &plusmn; 0.55 &mu;M, respectively. Both conjugates could effectively inhibit anti-ISGylation activities of PLpro in cells, and there is low toxicity of PDC EC-M and EM-C in different cells."
REF00595	PDC_02023	SARS-CoV infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	3.43 &plusmn; 0.54 &mu;M	&mu;M	.	.	.	.	COVID-19	SARS-CoV-2	.	.	.	.	.	"The enzymatic activities of SARS-CoV-2 PLpro were tested using the fluorogenic peptide substrate LRGG-AMC. The sulfonium-tethered peptides without GRL0617 could not efficiently inhibit SARS-CoV-2 PLpro, while the sulfonium-tethered peptide conjugate GRL0617 has a better inhibition ability. Specifically, IC50 values of EM-C and EC-M were 7.40 &plusmn; 0.37 and 8.63 &plusmn; 0.55 &mu;M, respectively. Enzymatic activities of PLpro were inhibited by different PDCs or GRL0617. (A) Enzymatic activity of SARS-CoV-2 PLpro was inhibited by different PDCs or GRL0617. The activity assay was performed using the peptide LRGG-ACC as a substrate. Error bars represent standard errors of mean of at least three independent measurements. (B) IC50 of different PDCs or GRL0617 in SARS-CoV-2 PLpro. IC50 of EM-C was 7.40 &plusmn; 0.37 &mu;M. IC50 of EC-M was 8.63 &plusmn; 0.55 &mu;M. IC50 of ELRGG was 15.38 &plusmn; 1.63 &mu;M. IC50 of GRL0617 was 2.64 &plusmn; 0.34 &mu;M. (C) Enzymatic activity of SARS-CoV PLpro was inhibited by different PDCs or GRL0617. (D) Enzyme activity of MERS PLpro was inhibited by different PDCs or GRL0617. Also, we tested the peptide inhibition ability to SARS-CoV PLpro and MERS PLpro. There is a high sequence identity (83%) between the SARS-CoV-2 PLpro and SARS-CoV PLpro. The IC50 value of EM-C against SARS-CoV PLpro was 3.43 &plusmn; 0.54 &mu;M, close to GRL0617 (IC50 = 2.60 &plusmn; 0.05 &mu;M). Its linear analogue showed weaker inhibition. The GRL0617, EC-M, EM-C, and ELRGG could not inhibit MERS PLpro. Both EM-C and EC-M showed better inhibition for SARS-CoV PLpro than SARS-CoV-2 PLpro."	"Peptide-drug conjugates (PDCs) are a class of novel molecules widely designed and synthesized for delivering drug payloads. In this work, we designed a novel PDC in which the GRL0617 was linked to the sulfonium-tethered peptides derived from PLpro-specific substrate LRGG. This conjugate could covalently label PLpro active site C111. Two conjugates EM-C and EC-M showed a promising in vitro IC50 of 7.40 &plusmn; 0.37 and 8.63 &plusmn; 0.55 &mu;M, respectively. Both conjugates could effectively inhibit anti-ISGylation activities of PLpro in cells, and there is low toxicity of PDC EC-M and EM-C in different cells."
REF00595	PDC_02024	SARS-CoV infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	31.75 &plusmn;1.55 &mu;M	&mu;M	.	.	.	.	COVID-19	SARS-CoV-2	.	.	.	.	.	"The enzymatic activities of SARS-CoV-2 PLpro were tested using the fluorogenic peptide substrate LRGG-AMC. The sulfonium-tethered peptides without GRL0617 could not efficiently inhibit SARS-CoV-2 PLpro, while the sulfonium-tethered peptide conjugate GRL0617 has a better inhibition ability. Specifically, IC50 values of EM-C and EC-M were 7.40 &plusmn; 0.37 and 8.63 &plusmn; 0.55 &mu;M, respectively. Enzymatic activities of PLpro were inhibited by different PDCs or GRL0617. (A) Enzymatic activity of SARS-CoV-2 PLpro was inhibited by different PDCs or GRL0617. The activity assay was performed using the peptide LRGG-ACC as a substrate. Error bars represent standard errors of mean of at least three independent measurements. (B) IC50 of different PDCs or GRL0617 in SARS-CoV-2 PLpro. IC50 of EM-C was 7.40 &plusmn; 0.37 &mu;M. IC50 of EC-M was 8.63 &plusmn; 0.55 &mu;M. IC50 of ELRGG was 15.38 &plusmn; 1.63 &mu;M. IC50 of GRL0617 was 2.64 &plusmn; 0.34 &mu;M. (C) Enzymatic activity of SARS-CoV PLpro was inhibited by different PDCs or GRL0617. (D) Enzyme activity of MERS PLpro was inhibited by different PDCs or GRL0617. Also, we tested the peptide inhibition ability to SARS-CoV PLpro and MERS PLpro. There is a high sequence identity (83%) between the SARS-CoV-2 PLpro and SARS-CoV PLpro. The IC50 value of EM-C against SARS-CoV PLpro was 3.43 &plusmn; 0.54 &mu;M, close to GRL0617 (IC50 = 2.60 &plusmn; 0.05 &mu;M). Its linear analogue showed weaker inhibition. The GRL0617, EC-M, EM-C, and ELRGG could not inhibit MERS PLpro. Both EM-C and EC-M showed better inhibition for SARS-CoV PLpro than SARS-CoV-2 PLpro."	"Peptide-drug conjugates (PDCs) are a class of novel molecules widely designed and synthesized for delivering drug payloads. In this work, we designed a novel PDC in which the GRL0617 was linked to the sulfonium-tethered peptides derived from PLpro-specific substrate LRGG. This conjugate could covalently label PLpro active site C111. Two conjugates EM-C and EC-M showed a promising in vitro IC50 of 7.40 &plusmn; 0.37 and 8.63 &plusmn; 0.55 &mu;M, respectively. Both conjugates could effectively inhibit anti-ISGylation activities of PLpro in cells, and there is low toxicity of PDC EC-M and EM-C in different cells."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	8.00%	%	.	.	Phase 2	81 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"The phase I arm established 40 mg of melflufen as the maximum tolerated dose in combination with dexamethasone. The phase II arm found an overall response rate (ORR) of 31% (14 patients) and clinical benefit rate, defined as first occurrence of disease response including minimal response or better, of 49% (22 patients) in the melflufen and dexamethasone group compared with an ORR of 8% (1 patient) and clinical benefit rate of 23% (3 patients) in the melflufen group. Based on these findings, melflufen 40 mg plus dexamethasone 40 mg was deemed a feasible treatment regimen for relapsed and refractory multiple myeloma and appropriate to proceed to a larger phase II trial."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Clinical benefit rate	23%	%	.	.	Phase 2	81 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"The phase I arm established 40 mg of melflufen as the maximum tolerated dose in combination with dexamethasone. The phase II arm found an overall response rate (ORR) of 31% (14 patients) and clinical benefit rate, defined as first occurrence of disease response including minimal response or better, of 49% (22 patients) in the melflufen and dexamethasone group compared with an ORR of 8% (1 patient) and clinical benefit rate of 23% (3 patients) in the melflufen group. Based on these findings, melflufen 40 mg plus dexamethasone 40 mg was deemed a feasible treatment regimen for relapsed and refractory multiple myeloma and appropriate to proceed to a larger phase II trial."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	29.00%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"The primary outcome of the study was ORR, defined based on the International Myeloma Working Group (IMWG) uniform response criteria. Investigators included a preplanned subgroup analysis in patients with triple-class refractory disease defined as refractory to at least 1 immunomodulator, 1 proteosome inhibitor, and 1 anti-CD38 antibody. From December 28, 2016, to October 14, 2019, investigators enrolled 157 patients across 17 sites that received at least 1 dose of melflufen. Patient baseline demographics included median age of 65 years old, an average of 5 previous lines of therapy, and 98% of patients were refractory to their previous line of therapy. A total of 131 patients (83%) discontinued treatment due to either disease progression or adverse effects. The median ORR was 29% (22%-37%) for the all treatment group and 26% (18%-35%) in the triple-class refractory disease group. The median duration of at least partial response or better was 5.5 months (3.9-7.6 months) in the all treatment group and 4.4 months (3.4-7.6 months) in the triple-class refractory disease group. Median overall survival (OS) was 11.6 months (9.3-15.4 months) in the all treatment group and 16.5 months (11.5-18.5 months) in the triple-class refractory group."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median duration of response	5.5 months	months	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"The primary outcome of the study was ORR, defined based on the International Myeloma Working Group (IMWG) uniform response criteria. Investigators included a preplanned subgroup analysis in patients with triple-class refractory disease defined as refractory to at least 1 immunomodulator, 1 proteosome inhibitor, and 1 anti-CD38 antibody. From December 28, 2016, to October 14, 2019, investigators enrolled 157 patients across 17 sites that received at least 1 dose of melflufen. Patient baseline demographics included median age of 65 years old, an average of 5 previous lines of therapy, and 98% of patients were refractory to their previous line of therapy. A total of 131 patients (83%) discontinued treatment due to either disease progression or adverse effects. The median ORR was 29% (22%-37%) for the all treatment group and 26% (18%-35%) in the triple-class refractory disease group. The median duration of at least partial response or better was 5.5 months (3.9-7.6 months) in the all treatment group and 4.4 months (3.4-7.6 months) in the triple-class refractory disease group. Median overall survival (OS) was 11.6 months (9.3-15.4 months) in the all treatment group and 16.5 months (11.5-18.5 months) in the triple-class refractory group."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	11.6 months	months	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"The primary outcome of the study was ORR, defined based on the International Myeloma Working Group (IMWG) uniform response criteria. Investigators included a preplanned subgroup analysis in patients with triple-class refractory disease defined as refractory to at least 1 immunomodulator, 1 proteosome inhibitor, and 1 anti-CD38 antibody. From December 28, 2016, to October 14, 2019, investigators enrolled 157 patients across 17 sites that received at least 1 dose of melflufen. Patient baseline demographics included median age of 65 years old, an average of 5 previous lines of therapy, and 98% of patients were refractory to their previous line of therapy. A total of 131 patients (83%) discontinued treatment due to either disease progression or adverse effects. The median ORR was 29% (22%-37%) for the all treatment group and 26% (18%-35%) in the triple-class refractory disease group. The median duration of at least partial response or better was 5.5 months (3.9-7.6 months) in the all treatment group and 4.4 months (3.4-7.6 months) in the triple-class refractory disease group. Median overall survival (OS) was 11.6 months (9.3-15.4 months) in the all treatment group and 16.5 months (11.5-18.5 months) in the triple-class refractory group."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	26%	%	.	.	Phase 2	Patients with triple-class refractory disease group multiple myeloma.	.	.	.	.	.	40 mg	.	"The primary outcome of the study was ORR, defined based on the International Myeloma Working Group (IMWG) uniform response criteria. Investigators included a preplanned subgroup analysis in patients with triple-class refractory disease defined as refractory to at least 1 immunomodulator, 1 proteosome inhibitor, and 1 anti-CD38 antibody. From December 28, 2016, to October 14, 2019, investigators enrolled 157 patients across 17 sites that received at least 1 dose of melflufen. Patient baseline demographics included median age of 65 years old, an average of 5 previous lines of therapy, and 98% of patients were refractory to their previous line of therapy. A total of 131 patients (83%) discontinued treatment due to either disease progression or adverse effects. The median ORR was 29% (22%-37%) for the all treatment group and 26% (18%-35%) in the triple-class refractory disease group. The median duration of at least partial response or better was 5.5 months (3.9-7.6 months) in the all treatment group and 4.4 months (3.4-7.6 months) in the triple-class refractory disease group. Median overall survival (OS) was 11.6 months (9.3-15.4 months) in the all treatment group and 16.5 months (11.5-18.5 months) in the triple-class refractory group."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median duration of response	4.4 months	months	.	.	Phase 2	Patients with triple-class refractory disease group multiple myeloma.	.	.	.	.	.	40 mg	.	"The primary outcome of the study was ORR, defined based on the International Myeloma Working Group (IMWG) uniform response criteria. Investigators included a preplanned subgroup analysis in patients with triple-class refractory disease defined as refractory to at least 1 immunomodulator, 1 proteosome inhibitor, and 1 anti-CD38 antibody. From December 28, 2016, to October 14, 2019, investigators enrolled 157 patients across 17 sites that received at least 1 dose of melflufen. Patient baseline demographics included median age of 65 years old, an average of 5 previous lines of therapy, and 98% of patients were refractory to their previous line of therapy. A total of 131 patients (83%) discontinued treatment due to either disease progression or adverse effects. The median ORR was 29% (22%-37%) for the all treatment group and 26% (18%-35%) in the triple-class refractory disease group. The median duration of at least partial response or better was 5.5 months (3.9-7.6 months) in the all treatment group and 4.4 months (3.4-7.6 months) in the triple-class refractory disease group. Median overall survival (OS) was 11.6 months (9.3-15.4 months) in the all treatment group and 16.5 months (11.5-18.5 months) in the triple-class refractory group."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	16.5 months	months	.	.	Phase 2	Patients with triple-class refractory disease group multiple myeloma.	.	.	.	.	.	40 mg	.	"The primary outcome of the study was ORR, defined based on the International Myeloma Working Group (IMWG) uniform response criteria. Investigators included a preplanned subgroup analysis in patients with triple-class refractory disease defined as refractory to at least 1 immunomodulator, 1 proteosome inhibitor, and 1 anti-CD38 antibody. From December 28, 2016, to October 14, 2019, investigators enrolled 157 patients across 17 sites that received at least 1 dose of melflufen. Patient baseline demographics included median age of 65 years old, an average of 5 previous lines of therapy, and 98% of patients were refractory to their previous line of therapy. A total of 131 patients (83%) discontinued treatment due to either disease progression or adverse effects. The median ORR was 29% (22%-37%) for the all treatment group and 26% (18%-35%) in the triple-class refractory disease group. The median duration of at least partial response or better was 5.5 months (3.9-7.6 months) in the all treatment group and 4.4 months (3.4-7.6 months) in the triple-class refractory disease group. Median overall survival (OS) was 11.6 months (9.3-15.4 months) in the all treatment group and 16.5 months (11.5-18.5 months) in the triple-class refractory group."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	19.7 months	months	.	.	Phase 3	Patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"The FDA announced on July 28, 2021, all ongoing melflufen clinical trials are to suspend enrollment until a complete safety analysis can be performed. This recommendation is based on preliminary OCEAN trial OS data. The hazard ratio for OS was 1.104 (0.846-1.441) when comparing the 2 treatment arms, favoring pomalidomide plus dexamethasone. At a median follow-up of 19.1 months, the median OS for the melflufen arm was 19.7 months (15.1-25.6) compared with 25 months (18.1-31.9) in the pomalidomide arm. At this time, no further recommendations have been made by the FDA concerning the continuation of melflufen clinical trials."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	100.00%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"Based on the safety data collected during the HORIZON trial, treatment emergent adverse events occurred in 100% of patients including 100 patients (64%) having at least 1 CTCAE grade 4 adverse effect. Hematologic grade 3 or 4 adverse effects including thrombocytopenia (76%), neutropenia (79%), anemia (43%), and infections (11%) were the most commonly reported. Other adverse effects, such as fatigue (55%), nausea (32%), diarrhea (27%), and decreased appetite (14%), were similar to other alkylating agents. Pyrexia (24%), including febrile neutropenia (5%), and respiratory tract infections (24%) were contributed to hematologic toxicities."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 4 adverse effect	64%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"Based on the safety data collected during the HORIZON trial, treatment emergent adverse events occurred in 100% of patients including 100 patients (64%) having at least 1 CTCAE grade 4 adverse effect. Hematologic grade 3 or 4 adverse effects including thrombocytopenia (76%), neutropenia (79%), anemia (43%), and infections (11%) were the most commonly reported. Other adverse effects, such as fatigue (55%), nausea (32%), diarrhea (27%), and decreased appetite (14%), were similar to other alkylating agents. Pyrexia (24%), including febrile neutropenia (5%), and respiratory tract infections (24%) were contributed to hematologic toxicities."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	76.00%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"Based on the safety data collected during the HORIZON trial, treatment emergent adverse events occurred in 100% of patients including 100 patients (64%) having at least 1 CTCAE grade 4 adverse effect. Hematologic grade 3 or 4 adverse effects including thrombocytopenia (76%), neutropenia (79%), anemia (43%), and infections (11%) were the most commonly reported. Other adverse effects, such as fatigue (55%), nausea (32%), diarrhea (27%), and decreased appetite (14%), were similar to other alkylating agents. Pyrexia (24%), including febrile neutropenia (5%), and respiratory tract infections (24%) were contributed to hematologic toxicities."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Neutropenia	79.00%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"Based on the safety data collected during the HORIZON trial, treatment emergent adverse events occurred in 100% of patients including 100 patients (64%) having at least 1 CTCAE grade 4 adverse effect. Hematologic grade 3 or 4 adverse effects including thrombocytopenia (76%), neutropenia (79%), anemia (43%), and infections (11%) were the most commonly reported. Other adverse effects, such as fatigue (55%), nausea (32%), diarrhea (27%), and decreased appetite (14%), were similar to other alkylating agents. Pyrexia (24%), including febrile neutropenia (5%), and respiratory tract infections (24%) were contributed to hematologic toxicities."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Anemia	43.00%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"Based on the safety data collected during the HORIZON trial, treatment emergent adverse events occurred in 100% of patients including 100 patients (64%) having at least 1 CTCAE grade 4 adverse effect. Hematologic grade 3 or 4 adverse effects including thrombocytopenia (76%), neutropenia (79%), anemia (43%), and infections (11%) were the most commonly reported. Other adverse effects, such as fatigue (55%), nausea (32%), diarrhea (27%), and decreased appetite (14%), were similar to other alkylating agents. Pyrexia (24%), including febrile neutropenia (5%), and respiratory tract infections (24%) were contributed to hematologic toxicities."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Infection rate	11%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"Based on the safety data collected during the HORIZON trial, treatment emergent adverse events occurred in 100% of patients including 100 patients (64%) having at least 1 CTCAE grade 4 adverse effect. Hematologic grade 3 or 4 adverse effects including thrombocytopenia (76%), neutropenia (79%), anemia (43%), and infections (11%) were the most commonly reported. Other adverse effects, such as fatigue (55%), nausea (32%), diarrhea (27%), and decreased appetite (14%), were similar to other alkylating agents. Pyrexia (24%), including febrile neutropenia (5%), and respiratory tract infections (24%) were contributed to hematologic toxicities."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Fatigue	55%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"Based on the safety data collected during the HORIZON trial, treatment emergent adverse events occurred in 100% of patients including 100 patients (64%) having at least 1 CTCAE grade 4 adverse effect. Hematologic grade 3 or 4 adverse effects including thrombocytopenia (76%), neutropenia (79%), anemia (43%), and infections (11%) were the most commonly reported. Other adverse effects, such as fatigue (55%), nausea (32%), diarrhea (27%), and decreased appetite (14%), were similar to other alkylating agents. Pyrexia (24%), including febrile neutropenia (5%), and respiratory tract infections (24%) were contributed to hematologic toxicities."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Nausea	32.00%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"Based on the safety data collected during the HORIZON trial, treatment emergent adverse events occurred in 100% of patients including 100 patients (64%) having at least 1 CTCAE grade 4 adverse effect. Hematologic grade 3 or 4 adverse effects including thrombocytopenia (76%), neutropenia (79%), anemia (43%), and infections (11%) were the most commonly reported. Other adverse effects, such as fatigue (55%), nausea (32%), diarrhea (27%), and decreased appetite (14%), were similar to other alkylating agents. Pyrexia (24%), including febrile neutropenia (5%), and respiratory tract infections (24%) were contributed to hematologic toxicities."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Diarrhea	27%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"Based on the safety data collected during the HORIZON trial, treatment emergent adverse events occurred in 100% of patients including 100 patients (64%) having at least 1 CTCAE grade 4 adverse effect. Hematologic grade 3 or 4 adverse effects including thrombocytopenia (76%), neutropenia (79%), anemia (43%), and infections (11%) were the most commonly reported. Other adverse effects, such as fatigue (55%), nausea (32%), diarrhea (27%), and decreased appetite (14%), were similar to other alkylating agents. Pyrexia (24%), including febrile neutropenia (5%), and respiratory tract infections (24%) were contributed to hematologic toxicities."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Decreased appetite 	14%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"Based on the safety data collected during the HORIZON trial, treatment emergent adverse events occurred in 100% of patients including 100 patients (64%) having at least 1 CTCAE grade 4 adverse effect. Hematologic grade 3 or 4 adverse effects including thrombocytopenia (76%), neutropenia (79%), anemia (43%), and infections (11%) were the most commonly reported. Other adverse effects, such as fatigue (55%), nausea (32%), diarrhea (27%), and decreased appetite (14%), were similar to other alkylating agents. Pyrexia (24%), including febrile neutropenia (5%), and respiratory tract infections (24%) were contributed to hematologic toxicities."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Pyrexia	24%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"Based on the safety data collected during the HORIZON trial, treatment emergent adverse events occurred in 100% of patients including 100 patients (64%) having at least 1 CTCAE grade 4 adverse effect. Hematologic grade 3 or 4 adverse effects including thrombocytopenia (76%), neutropenia (79%), anemia (43%), and infections (11%) were the most commonly reported. Other adverse effects, such as fatigue (55%), nausea (32%), diarrhea (27%), and decreased appetite (14%), were similar to other alkylating agents. Pyrexia (24%), including febrile neutropenia (5%), and respiratory tract infections (24%) were contributed to hematologic toxicities."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Neutropenia	5.00%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"Based on the safety data collected during the HORIZON trial, treatment emergent adverse events occurred in 100% of patients including 100 patients (64%) having at least 1 CTCAE grade 4 adverse effect. Hematologic grade 3 or 4 adverse effects including thrombocytopenia (76%), neutropenia (79%), anemia (43%), and infections (11%) were the most commonly reported. Other adverse effects, such as fatigue (55%), nausea (32%), diarrhea (27%), and decreased appetite (14%), were similar to other alkylating agents. Pyrexia (24%), including febrile neutropenia (5%), and respiratory tract infections (24%) were contributed to hematologic toxicities."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00594	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Respiratory tract infection	24%	%	.	.	Phase 2	157 patients with multiple myeloma.	.	.	.	.	.	40 mg	.	"Based on the safety data collected during the HORIZON trial, treatment emergent adverse events occurred in 100% of patients including 100 patients (64%) having at least 1 CTCAE grade 4 adverse effect. Hematologic grade 3 or 4 adverse effects including thrombocytopenia (76%), neutropenia (79%), anemia (43%), and infections (11%) were the most commonly reported. Other adverse effects, such as fatigue (55%), nausea (32%), diarrhea (27%), and decreased appetite (14%), were similar to other alkylating agents. Pyrexia (24%), including febrile neutropenia (5%), and respiratory tract infections (24%) were contributed to hematologic toxicities."	"Melflufen is a first-in-class peptide-drug conjugate, targeting aminopeptidase which has an increased expression in fast-growing and aggressive malignancies. The lipophilicity of melflufen allows for passive diffusion, selectively targeting myeloma cells. Once inside the cell, melflufen is hydrolyzed to active alkylating metabolites melphalan and desethyl-melflufen. Melflufen and the active metabolites trigger irreversible DNA damage, inhibit proliferation, induces apoptosis, and express antiangiogenic effects. In addition, melflufen demonstrated activity in myeloma cells with documented impaired or absent Tp53 expression and documented resistance to bortezomib, dexamethasone, and melphalan."
REF00593	PDC_02025	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	76.00%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	0.156 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02025	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	61.00%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	0.625 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02025	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	53.00%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	2.5 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02025	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	33.00%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	10 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02026	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	85.00%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	0.156 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02026	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	78.00%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	0.625 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02026	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	69.00%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	2.5 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02026	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	45.00%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	10 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02027	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	98.00%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	0.156 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02027	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	99.00%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	0.625 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02027	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	90.00%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	2.5 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02027	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	70.00%	%	.	.	.	.	Breast adenocarcinoma	SK-BR-3 cell	.	.	48 h	10 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02025	Gastric tubular adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	85.00%	%	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	0.156 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02025	Gastric tubular adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	82.00%	%	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	0.625 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02025	Gastric tubular adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	53.00%	%	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	2.5 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02025	Gastric tubular adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	44.00%	%	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	10 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02026	Gastric tubular adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	100.00%	%	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	0.156 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02026	Gastric tubular adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	80.00%	%	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	0.625 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02026	Gastric tubular adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	62.00%	%	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	2.5 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02026	Gastric tubular adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	45.00%	%	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	10 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02027	Gastric tubular adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	100.00%	%	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	0.156 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02027	Gastric tubular adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	100.00%	%	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	0.625 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02027	Gastric tubular adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	100.00%	%	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	2.5 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00593	PDC_02027	Gastric tubular adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	90.00%	%	.	.	.	.	Gastric tubular adenocarcinoma	NCI-N87 cell	.	.	48 h	10 &mu;M	CCK-8 assay	"Antiproliferative activity of conjugates were evaluated using HER2-positive SK-BR-3 and NCI-N87 cells. As shown in Fig. 5A, Conjugate 1 reduced the cell viability by 23, 38, 47 and 66% at 0.156, 0.625, 2.5 and 10 &mu;M. Its cytotoxicity is significantly more than Conjugate 2 at 0.625 &mu;M and 10 &mu;M. It showed comparable cytotoxicity with CPT at 10 &mu;M. And Conjugate 3 showed little cytotoxicity at any concentrations other than 10 &mu;M, which may be related to the structure of Conjugate 3 where CPT is conjugated on the peptide by non-breakable bond preventing CPT from acting as an anticancer agent. Cyclo-GCGPep1 exhibited no significant cytotoxicity at any concentrations indicating that peptide part of PDCs is inactive for inducing cancer cell death. Similar results can be seen on NCI-N87 cells. Conjugate 1 reduced significantly more cell viability than Conjugate 2 at 0.156 &mu;M and 2.5 &mu;M. And Conjugate 1 exhibited comparable antiproliferation activity as CPT at 2.5 &mu;M and 10 &mu;M. The cytotoxicity of Conjugate 3 is still weak at any concentrations. Cyclo-GCGPep1 is non-toxic to NCI-N87 cells as well. These results told us antiproliferative activity of conjugates is closely related to the ways drugs are conjugated. The cleavable disulfide bonds in Conjugate 1 and 2 could be broken and then Camptothecin derivatives can be released in cells, which is much related to anti-proliferative activity. In general, Conjugate 1 showed best antiproliferative activity and it was selected for further research."	"In this research, based on the binding mode between Trastuzumab and HER2 protein, we first discovered a peptide sequence Leadpep that plays a vital role when antibody binds with HER2 protein. In silico mutations were conducted on Leadpep to screen out HER2-targeted peptides. The binding affinity of Cyclo-GCGPep1 increased when cyclized (Kd = 2.555 10<sup>-6</sup>M). It was used for constructing PDCs with the cytotoxin Camptothecin. Among them, Conjugate 1 showed best antiproliferative activities. Further research demonstrated that Conjugate 1 has a similar mechanism to Camptothecin. It is worth noting that Conjugate 1 showed a good specific delivery capacity and better penetration than Camptothecin. It could be a new therapeutic tool for HER2-positive cancer."
REF00592	PDC_02028	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	616.1 nM	nM	.	.	.	.	Normal	HEK-293T (ACE-) cell	5.82 h	.	.	.	MTT assay	"To evaluate the in vitro antitumor activity, BPP-PTX, uncoupled peptide (BPP), and PTX were under cytotoxicity evaluation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazole (MTT) assay in ACE-positive TNBC cell lines (MDA-MB-231 and MDA-MB-468) and ACE-negative cell lines (HEK293T). The free BPP peptide did not exhibit any cytotoxicity in all cell lines. In contrast, the IC50 value of BPP-PTX in ACE-negative HEK293T was 616.1 nM [95% CI, (242.7, 1564.0)], which was much higher than that of PTX in the same cell line {6.7 nM [95% CI, (5.3, 8.4)]}. Interestingly, the cytotoxicity of BPP-PTX was comparable with that of PTX in ACE-positive TNBC cell lines. In MDA-MB-231, the IC50 value of BPP-PTX was 9.5 nM [95% CI, (7.0, 12.8)], and that of PTX was 3.1 nM [95% CI, (2.8, 3.5)]. In MDA-MB-468, the IC50 value of BPP-PTX was 12.3 nM [95% CI, (6.8, 22.3)], and that of PTX was 3.0 nM [95% CI, (2.0, 4.7)]."	"Here, we report the design, synthesis, and evaluation-in vitro and in vivo-of a novel PDC, namely BPP-PTX, whereby PTX is conjugated to one member of BPPs, Bj-BPP-9a (teprotide), via a succinyl linker. The targeting moiety was carefully selected based on previous studies. It was similarly employed with a nanoparticle carrier in vivo and was shown to modulate improved drug accumulation at the tumor site, thereby curbing tumor growth and extending the lives of tumor-bearing mice. In this study, we demonstrate for the first time that BPP-PTX functions through BPPs cognate receptor, ACE. ACE was overexpressed in TNBC cell lines but not in the receptor-positive cell line. BPP, as part of BPP-PTX, bound ACE and mediated its selective cytotoxic action through this receptor in ACE-positive TNBC cells. Furthermore, BPP-PTX demonstrated improved biodistribution, therapeutic activity, and better safety profile in vivo. These results advocate the significance of BPP-PTX as a suitable tumor-targeting PDC, strongly warranting further refinement and investigations for TNBC."
REF00592	PDC_02028	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	9.5 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 (ACE+) cell	5.82 h	.	.	.	MTT assay	"To evaluate the in vitro antitumor activity, BPP-PTX, uncoupled peptide (BPP), and PTX were under cytotoxicity evaluation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazole (MTT) assay in ACE-positive TNBC cell lines (MDA-MB-231 and MDA-MB-468) and ACE-negative cell lines (HEK293T). The free BPP peptide did not exhibit any cytotoxicity in all cell lines. In contrast, the IC50 value of BPP-PTX in ACE-negative HEK293T was 616.1 nM [95% CI, (242.7, 1564.0)], which was much higher than that of PTX in the same cell line {6.7 nM [95% CI, (5.3, 8.4)]}. Interestingly, the cytotoxicity of BPP-PTX was comparable with that of PTX in ACE-positive TNBC cell lines. In MDA-MB-231, the IC50 value of BPP-PTX was 9.5 nM [95% CI, (7.0, 12.8)], and that of PTX was 3.1 nM [95% CI, (2.8, 3.5)]. In MDA-MB-468, the IC50 value of BPP-PTX was 12.3 nM [95% CI, (6.8, 22.3)], and that of PTX was 3.0 nM [95% CI, (2.0, 4.7)]."	"Here, we report the design, synthesis, and evaluation-in vitro and in vivo-of a novel PDC, namely BPP-PTX, whereby PTX is conjugated to one member of BPPs, Bj-BPP-9a (teprotide), via a succinyl linker. The targeting moiety was carefully selected based on previous studies. It was similarly employed with a nanoparticle carrier in vivo and was shown to modulate improved drug accumulation at the tumor site, thereby curbing tumor growth and extending the lives of tumor-bearing mice. In this study, we demonstrate for the first time that BPP-PTX functions through BPPs cognate receptor, ACE. ACE was overexpressed in TNBC cell lines but not in the receptor-positive cell line. BPP, as part of BPP-PTX, bound ACE and mediated its selective cytotoxic action through this receptor in ACE-positive TNBC cells. Furthermore, BPP-PTX demonstrated improved biodistribution, therapeutic activity, and better safety profile in vivo. These results advocate the significance of BPP-PTX as a suitable tumor-targeting PDC, strongly warranting further refinement and investigations for TNBC."
REF00592	PDC_02028	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	12.3 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	5.82 h	.	.	.	MTT assay	"To evaluate the in vitro antitumor activity, BPP-PTX, uncoupled peptide (BPP), and PTX were under cytotoxicity evaluation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazole (MTT) assay in ACE-positive TNBC cell lines (MDA-MB-231 and MDA-MB-468) and ACE-negative cell lines (HEK293T). The free BPP peptide did not exhibit any cytotoxicity in all cell lines. In contrast, the IC50 value of BPP-PTX in ACE-negative HEK293T was 616.1 nM [95% CI, (242.7, 1564.0)], which was much higher than that of PTX in the same cell line {6.7 nM [95% CI, (5.3, 8.4)]}. Interestingly, the cytotoxicity of BPP-PTX was comparable with that of PTX in ACE-positive TNBC cell lines. In MDA-MB-231, the IC50 value of BPP-PTX was 9.5 nM [95% CI, (7.0, 12.8)], and that of PTX was 3.1 nM [95% CI, (2.8, 3.5)]. In MDA-MB-468, the IC50 value of BPP-PTX was 12.3 nM [95% CI, (6.8, 22.3)], and that of PTX was 3.0 nM [95% CI, (2.0, 4.7)]."	"Here, we report the design, synthesis, and evaluation-in vitro and in vivo-of a novel PDC, namely BPP-PTX, whereby PTX is conjugated to one member of BPPs, Bj-BPP-9a (teprotide), via a succinyl linker. The targeting moiety was carefully selected based on previous studies. It was similarly employed with a nanoparticle carrier in vivo and was shown to modulate improved drug accumulation at the tumor site, thereby curbing tumor growth and extending the lives of tumor-bearing mice. In this study, we demonstrate for the first time that BPP-PTX functions through BPPs cognate receptor, ACE. ACE was overexpressed in TNBC cell lines but not in the receptor-positive cell line. BPP, as part of BPP-PTX, bound ACE and mediated its selective cytotoxic action through this receptor in ACE-positive TNBC cells. Furthermore, BPP-PTX demonstrated improved biodistribution, therapeutic activity, and better safety profile in vivo. These results advocate the significance of BPP-PTX as a suitable tumor-targeting PDC, strongly warranting further refinement and investigations for TNBC."
REF00592	PDC_02028	Triple-negative breast cancer	Female BALB/c mice.	Obtained from the Model Organism Data	High Expreesion	Weight loss rate	1.90%	%	.	.	.	.	.	.	5.82 h	.	.	60 mg/kg	.	"After obtaining positive in vitro results, BPP-PTX was then tested in vivo. To test the in vivo toxicity of the drug, the maximum tolerated dose (MTD) of BPP-PTX in Balb/c mice was determined. The single-dose MTD (acute toxicity) of plain PTX was 20 mg/kg (equivalent to 23.4 &mu;mol/kg), similar to previous findings in the literature, while the single-dose MTD of BPP-PTX was 100 mg/kg (equivalent to 48.7 &mu;mol/kg). The weight loss was more severe as the drug dose increased. However, the acute weight loss caused by high dose was temporary, with the body weight recovering to baseline levels within 15 days. Then, we evaluated the plasma pharmacokinetics profiles of plain PTX and BPP-PTX. Mice xenografted with MDA-MB-468 received intraperitoneal (i.p.) injections of 15 mg/kg PTX (equivalent to 17.6 &mu;mol/kg) or 36.1 mg/kg BPP-PTX (equivalent to 17.6 &mu;mol/kg). The plasma PTX concentration in the plain PTX-treated group reached peak levels at 1 h and then decreased rapidly, and it was quickly removed from the circulating system. In contrast, the plasma PTX concentration in the BPP-PTX-treated group remained high for an extended period after 1 h, suggesting that BPP-PTX could have a lower release rate in circulation."	"Here, we report the design, synthesis, and evaluation-in vitro and in vivo-of a novel PDC, namely BPP-PTX, whereby PTX is conjugated to one member of BPPs, Bj-BPP-9a (teprotide), via a succinyl linker. The targeting moiety was carefully selected based on previous studies. It was similarly employed with a nanoparticle carrier in vivo and was shown to modulate improved drug accumulation at the tumor site, thereby curbing tumor growth and extending the lives of tumor-bearing mice. In this study, we demonstrate for the first time that BPP-PTX functions through BPPs cognate receptor, ACE. ACE was overexpressed in TNBC cell lines but not in the receptor-positive cell line. BPP, as part of BPP-PTX, bound ACE and mediated its selective cytotoxic action through this receptor in ACE-positive TNBC cells. Furthermore, BPP-PTX demonstrated improved biodistribution, therapeutic activity, and better safety profile in vivo. These results advocate the significance of BPP-PTX as a suitable tumor-targeting PDC, strongly warranting further refinement and investigations for TNBC."
REF00592	PDC_02028	Triple-negative breast cancer	Female BALB/c mice.	Obtained from the Model Organism Data	High Expreesion	Weight loss rate	4.50%	%	.	.	.	.	.	.	5.82 h	.	.	80 mg/kg	.	"After obtaining positive in vitro results, BPP-PTX was then tested in vivo. To test the in vivo toxicity of the drug, the maximum tolerated dose (MTD) of BPP-PTX in Balb/c mice was determined. The single-dose MTD (acute toxicity) of plain PTX was 20 mg/kg (equivalent to 23.4 &mu;mol/kg), similar to previous findings in the literature, while the single-dose MTD of BPP-PTX was 100 mg/kg (equivalent to 48.7 &mu;mol/kg). The weight loss was more severe as the drug dose increased. However, the acute weight loss caused by high dose was temporary, with the body weight recovering to baseline levels within 15 days. Then, we evaluated the plasma pharmacokinetics profiles of plain PTX and BPP-PTX. Mice xenografted with MDA-MB-468 received intraperitoneal (i.p.) injections of 15 mg/kg PTX (equivalent to 17.6 &mu;mol/kg) or 36.1 mg/kg BPP-PTX (equivalent to 17.6 &mu;mol/kg). The plasma PTX concentration in the plain PTX-treated group reached peak levels at 1 h and then decreased rapidly, and it was quickly removed from the circulating system. In contrast, the plasma PTX concentration in the BPP-PTX-treated group remained high for an extended period after 1 h, suggesting that BPP-PTX could have a lower release rate in circulation."	"Here, we report the design, synthesis, and evaluation-in vitro and in vivo-of a novel PDC, namely BPP-PTX, whereby PTX is conjugated to one member of BPPs, Bj-BPP-9a (teprotide), via a succinyl linker. The targeting moiety was carefully selected based on previous studies. It was similarly employed with a nanoparticle carrier in vivo and was shown to modulate improved drug accumulation at the tumor site, thereby curbing tumor growth and extending the lives of tumor-bearing mice. In this study, we demonstrate for the first time that BPP-PTX functions through BPPs cognate receptor, ACE. ACE was overexpressed in TNBC cell lines but not in the receptor-positive cell line. BPP, as part of BPP-PTX, bound ACE and mediated its selective cytotoxic action through this receptor in ACE-positive TNBC cells. Furthermore, BPP-PTX demonstrated improved biodistribution, therapeutic activity, and better safety profile in vivo. These results advocate the significance of BPP-PTX as a suitable tumor-targeting PDC, strongly warranting further refinement and investigations for TNBC."
REF00592	PDC_02028	Triple-negative breast cancer	Female BALB/c mice.	Obtained from the Model Organism Data	High Expreesion	Weight loss rate	7.20%	%	.	.	.	.	.	.	5.82 h	.	.	100 mg/kg	.	"After obtaining positive in vitro results, BPP-PTX was then tested in vivo. To test the in vivo toxicity of the drug, the maximum tolerated dose (MTD) of BPP-PTX in Balb/c mice was determined. The single-dose MTD (acute toxicity) of plain PTX was 20 mg/kg (equivalent to 23.4 &mu;mol/kg), similar to previous findings in the literature, while the single-dose MTD of BPP-PTX was 100 mg/kg (equivalent to 48.7 &mu;mol/kg). The weight loss was more severe as the drug dose increased. However, the acute weight loss caused by high dose was temporary, with the body weight recovering to baseline levels within 15 days. Then, we evaluated the plasma pharmacokinetics profiles of plain PTX and BPP-PTX. Mice xenografted with MDA-MB-468 received intraperitoneal (i.p.) injections of 15 mg/kg PTX (equivalent to 17.6 &mu;mol/kg) or 36.1 mg/kg BPP-PTX (equivalent to 17.6 &mu;mol/kg). The plasma PTX concentration in the plain PTX-treated group reached peak levels at 1 h and then decreased rapidly, and it was quickly removed from the circulating system. In contrast, the plasma PTX concentration in the BPP-PTX-treated group remained high for an extended period after 1 h, suggesting that BPP-PTX could have a lower release rate in circulation."	"Here, we report the design, synthesis, and evaluation-in vitro and in vivo-of a novel PDC, namely BPP-PTX, whereby PTX is conjugated to one member of BPPs, Bj-BPP-9a (teprotide), via a succinyl linker. The targeting moiety was carefully selected based on previous studies. It was similarly employed with a nanoparticle carrier in vivo and was shown to modulate improved drug accumulation at the tumor site, thereby curbing tumor growth and extending the lives of tumor-bearing mice. In this study, we demonstrate for the first time that BPP-PTX functions through BPPs cognate receptor, ACE. ACE was overexpressed in TNBC cell lines but not in the receptor-positive cell line. BPP, as part of BPP-PTX, bound ACE and mediated its selective cytotoxic action through this receptor in ACE-positive TNBC cells. Furthermore, BPP-PTX demonstrated improved biodistribution, therapeutic activity, and better safety profile in vivo. These results advocate the significance of BPP-PTX as a suitable tumor-targeting PDC, strongly warranting further refinement and investigations for TNBC."
REF00592	PDC_02028	Triple-negative breast cancer	Female BALB/c mice.	Obtained from the Model Organism Data	High Expreesion	Mice survival rate	100%	%	.	.	.	.	.	.	5.82 h	.	.	60 mg/kg	.	"After obtaining positive in vitro results, BPP-PTX was then tested in vivo. To test the in vivo toxicity of the drug, the maximum tolerated dose (MTD) of BPP-PTX in Balb/c mice was determined. The single-dose MTD (acute toxicity) of plain PTX was 20 mg/kg (equivalent to 23.4 &mu;mol/kg), similar to previous findings in the literature, while the single-dose MTD of BPP-PTX was 100 mg/kg (equivalent to 48.7 &mu;mol/kg). The weight loss was more severe as the drug dose increased. However, the acute weight loss caused by high dose was temporary, with the body weight recovering to baseline levels within 15 days. Then, we evaluated the plasma pharmacokinetics profiles of plain PTX and BPP-PTX. Mice xenografted with MDA-MB-468 received intraperitoneal (i.p.) injections of 15 mg/kg PTX (equivalent to 17.6 &mu;mol/kg) or 36.1 mg/kg BPP-PTX (equivalent to 17.6 &mu;mol/kg). The plasma PTX concentration in the plain PTX-treated group reached peak levels at 1 h and then decreased rapidly, and it was quickly removed from the circulating system. In contrast, the plasma PTX concentration in the BPP-PTX-treated group remained high for an extended period after 1 h, suggesting that BPP-PTX could have a lower release rate in circulation."	"Here, we report the design, synthesis, and evaluation-in vitro and in vivo-of a novel PDC, namely BPP-PTX, whereby PTX is conjugated to one member of BPPs, Bj-BPP-9a (teprotide), via a succinyl linker. The targeting moiety was carefully selected based on previous studies. It was similarly employed with a nanoparticle carrier in vivo and was shown to modulate improved drug accumulation at the tumor site, thereby curbing tumor growth and extending the lives of tumor-bearing mice. In this study, we demonstrate for the first time that BPP-PTX functions through BPPs cognate receptor, ACE. ACE was overexpressed in TNBC cell lines but not in the receptor-positive cell line. BPP, as part of BPP-PTX, bound ACE and mediated its selective cytotoxic action through this receptor in ACE-positive TNBC cells. Furthermore, BPP-PTX demonstrated improved biodistribution, therapeutic activity, and better safety profile in vivo. These results advocate the significance of BPP-PTX as a suitable tumor-targeting PDC, strongly warranting further refinement and investigations for TNBC."
REF00592	PDC_02028	Triple-negative breast cancer	Female BALB/c mice.	Obtained from the Model Organism Data	High Expreesion	Mice survival rate	100%	%	.	.	.	.	.	.	5.82 h	.	.	80 mg/kg	.	"After obtaining positive in vitro results, BPP-PTX was then tested in vivo. To test the in vivo toxicity of the drug, the maximum tolerated dose (MTD) of BPP-PTX in Balb/c mice was determined. The single-dose MTD (acute toxicity) of plain PTX was 20 mg/kg (equivalent to 23.4 &mu;mol/kg), similar to previous findings in the literature, while the single-dose MTD of BPP-PTX was 100 mg/kg (equivalent to 48.7 &mu;mol/kg). The weight loss was more severe as the drug dose increased. However, the acute weight loss caused by high dose was temporary, with the body weight recovering to baseline levels within 15 days. Then, we evaluated the plasma pharmacokinetics profiles of plain PTX and BPP-PTX. Mice xenografted with MDA-MB-468 received intraperitoneal (i.p.) injections of 15 mg/kg PTX (equivalent to 17.6 &mu;mol/kg) or 36.1 mg/kg BPP-PTX (equivalent to 17.6 &mu;mol/kg). The plasma PTX concentration in the plain PTX-treated group reached peak levels at 1 h and then decreased rapidly, and it was quickly removed from the circulating system. In contrast, the plasma PTX concentration in the BPP-PTX-treated group remained high for an extended period after 1 h, suggesting that BPP-PTX could have a lower release rate in circulation."	"Here, we report the design, synthesis, and evaluation-in vitro and in vivo-of a novel PDC, namely BPP-PTX, whereby PTX is conjugated to one member of BPPs, Bj-BPP-9a (teprotide), via a succinyl linker. The targeting moiety was carefully selected based on previous studies. It was similarly employed with a nanoparticle carrier in vivo and was shown to modulate improved drug accumulation at the tumor site, thereby curbing tumor growth and extending the lives of tumor-bearing mice. In this study, we demonstrate for the first time that BPP-PTX functions through BPPs cognate receptor, ACE. ACE was overexpressed in TNBC cell lines but not in the receptor-positive cell line. BPP, as part of BPP-PTX, bound ACE and mediated its selective cytotoxic action through this receptor in ACE-positive TNBC cells. Furthermore, BPP-PTX demonstrated improved biodistribution, therapeutic activity, and better safety profile in vivo. These results advocate the significance of BPP-PTX as a suitable tumor-targeting PDC, strongly warranting further refinement and investigations for TNBC."
REF00592	PDC_02028	Triple-negative breast cancer	Female BALB/c mice.	Obtained from the Model Organism Data	High Expreesion	Mice survival rate	100%	%	.	.	.	.	.	.	5.82 h	.	.	100 mg/kg	.	"After obtaining positive in vitro results, BPP-PTX was then tested in vivo. To test the in vivo toxicity of the drug, the maximum tolerated dose (MTD) of BPP-PTX in Balb/c mice was determined. The single-dose MTD (acute toxicity) of plain PTX was 20 mg/kg (equivalent to 23.4 &mu;mol/kg), similar to previous findings in the literature, while the single-dose MTD of BPP-PTX was 100 mg/kg (equivalent to 48.7 &mu;mol/kg). The weight loss was more severe as the drug dose increased. However, the acute weight loss caused by high dose was temporary, with the body weight recovering to baseline levels within 15 days. Then, we evaluated the plasma pharmacokinetics profiles of plain PTX and BPP-PTX. Mice xenografted with MDA-MB-468 received intraperitoneal (i.p.) injections of 15 mg/kg PTX (equivalent to 17.6 &mu;mol/kg) or 36.1 mg/kg BPP-PTX (equivalent to 17.6 &mu;mol/kg). The plasma PTX concentration in the plain PTX-treated group reached peak levels at 1 h and then decreased rapidly, and it was quickly removed from the circulating system. In contrast, the plasma PTX concentration in the BPP-PTX-treated group remained high for an extended period after 1 h, suggesting that BPP-PTX could have a lower release rate in circulation."	"Here, we report the design, synthesis, and evaluation-in vitro and in vivo-of a novel PDC, namely BPP-PTX, whereby PTX is conjugated to one member of BPPs, Bj-BPP-9a (teprotide), via a succinyl linker. The targeting moiety was carefully selected based on previous studies. It was similarly employed with a nanoparticle carrier in vivo and was shown to modulate improved drug accumulation at the tumor site, thereby curbing tumor growth and extending the lives of tumor-bearing mice. In this study, we demonstrate for the first time that BPP-PTX functions through BPPs cognate receptor, ACE. ACE was overexpressed in TNBC cell lines but not in the receptor-positive cell line. BPP, as part of BPP-PTX, bound ACE and mediated its selective cytotoxic action through this receptor in ACE-positive TNBC cells. Furthermore, BPP-PTX demonstrated improved biodistribution, therapeutic activity, and better safety profile in vivo. These results advocate the significance of BPP-PTX as a suitable tumor-targeting PDC, strongly warranting further refinement and investigations for TNBC."
REF00592	PDC_02028	Triple-negative breast cancer	Female BALB/c mice.	Obtained from the Model Organism Data	High Expreesion	Mice survival rate	75%	%	.	.	.	.	.	.	5.82 h	.	.	120 mg/kg	.	"After obtaining positive in vitro results, BPP-PTX was then tested in vivo. To test the in vivo toxicity of the drug, the maximum tolerated dose (MTD) of BPP-PTX in Balb/c mice was determined. The single-dose MTD (acute toxicity) of plain PTX was 20 mg/kg (equivalent to 23.4 &mu;mol/kg), similar to previous findings in the literature, while the single-dose MTD of BPP-PTX was 100 mg/kg (equivalent to 48.7 &mu;mol/kg). The weight loss was more severe as the drug dose increased. However, the acute weight loss caused by high dose was temporary, with the body weight recovering to baseline levels within 15 days. Then, we evaluated the plasma pharmacokinetics profiles of plain PTX and BPP-PTX. Mice xenografted with MDA-MB-468 received intraperitoneal (i.p.) injections of 15 mg/kg PTX (equivalent to 17.6 &mu;mol/kg) or 36.1 mg/kg BPP-PTX (equivalent to 17.6 &mu;mol/kg). The plasma PTX concentration in the plain PTX-treated group reached peak levels at 1 h and then decreased rapidly, and it was quickly removed from the circulating system. In contrast, the plasma PTX concentration in the BPP-PTX-treated group remained high for an extended period after 1 h, suggesting that BPP-PTX could have a lower release rate in circulation."	"Here, we report the design, synthesis, and evaluation-in vitro and in vivo-of a novel PDC, namely BPP-PTX, whereby PTX is conjugated to one member of BPPs, Bj-BPP-9a (teprotide), via a succinyl linker. The targeting moiety was carefully selected based on previous studies. It was similarly employed with a nanoparticle carrier in vivo and was shown to modulate improved drug accumulation at the tumor site, thereby curbing tumor growth and extending the lives of tumor-bearing mice. In this study, we demonstrate for the first time that BPP-PTX functions through BPPs cognate receptor, ACE. ACE was overexpressed in TNBC cell lines but not in the receptor-positive cell line. BPP, as part of BPP-PTX, bound ACE and mediated its selective cytotoxic action through this receptor in ACE-positive TNBC cells. Furthermore, BPP-PTX demonstrated improved biodistribution, therapeutic activity, and better safety profile in vivo. These results advocate the significance of BPP-PTX as a suitable tumor-targeting PDC, strongly warranting further refinement and investigations for TNBC."
REF00592	PDC_02028	Triple-negative breast cancer	TNBC nude mouse orthotopic transplantation tumor model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	64.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	5.82 h	.	30 days	2.4 &mu;mol/kg	.	"To test the in vivo efficacy and toxicity of BPP-PTX, an orthotopic mouse model was established. ACE-positive MDA-MB-468 cells were injected orthotopically into the mammary fat pad of female nude mice. After the inoculated tumors reached a mean volume of 100 mm<sup>3</sup>, they were randomly divided into four groups to ensure that the mean tumor volume was evaluated and treated for 28 days with PBS, plain PTX (2.4 &mu;mol/kg, equivalent to 2.0 mg/kg), low-dose BPP-PTX (2.4 &mu;mol/kg, equivalent to 4.9 mg/kg), and high-dose BPP-PTX (9.6 &mu;mol/kg, equivalent to 19.6 mg/kg) every 4 days by i.p. injection. Tumor growth was assessed by measuring tumor volume every 4 days. On the fourth day of testing after the first injection, there was no significant difference in tumor volume compared with control and drug-treated groups. In the subsequent treatments, the tumors of the control mice grew significantly faster than those of mice treated with plain PTX and BPP-PTX. On day 28, mice treated with low-dose BPP-PTX showed an approximately 15% reduction in mean tumor volume compared with mice treated with plain PTX and a 54% reduction compared to controls (PBS). Meanwhile, the mean tumor volumes of mice treated with high-dose BPP-PTX were reduced by 62% compared with control animals and by approximately 30% compared to animals treated with plain PTX. Consistently, the mean tumor weight of mice with low-dose BPP-PTX treatment was 0.20 g (0.17, 0.24), which is lower than that of mice treated with plain PTX [0.26 g (0.21, 0.31)] and control mice [0.43 g (0.37, 0.49)]. The tumor weight of mice treated with high-dose BPP-PTX was significantly lower than that of the control and plain PTX-treated groups, with a mean tumor weight of only 0.16 g (0.14, 0.19). These results suggested that BPP-PTX has good tumor-suppression efficacy in vivo, even better than that of plain PTX."	"Here, we report the design, synthesis, and evaluation-in vitro and in vivo-of a novel PDC, namely BPP-PTX, whereby PTX is conjugated to one member of BPPs, Bj-BPP-9a (teprotide), via a succinyl linker. The targeting moiety was carefully selected based on previous studies. It was similarly employed with a nanoparticle carrier in vivo and was shown to modulate improved drug accumulation at the tumor site, thereby curbing tumor growth and extending the lives of tumor-bearing mice. In this study, we demonstrate for the first time that BPP-PTX functions through BPPs cognate receptor, ACE. ACE was overexpressed in TNBC cell lines but not in the receptor-positive cell line. BPP, as part of BPP-PTX, bound ACE and mediated its selective cytotoxic action through this receptor in ACE-positive TNBC cells. Furthermore, BPP-PTX demonstrated improved biodistribution, therapeutic activity, and better safety profile in vivo. These results advocate the significance of BPP-PTX as a suitable tumor-targeting PDC, strongly warranting further refinement and investigations for TNBC."
REF00592	PDC_02028	Triple-negative breast cancer	TNBC nude mouse orthotopic transplantation tumor model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	74.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-468 cell	5.82 h	.	30 days	9.6 &mu;mol/kg	.	"To test the in vivo efficacy and toxicity of BPP-PTX, an orthotopic mouse model was established. ACE-positive MDA-MB-468 cells were injected orthotopically into the mammary fat pad of female nude mice. After the inoculated tumors reached a mean volume of 100 mm<sup>3</sup>, they were randomly divided into four groups to ensure that the mean tumor volume was evaluated and treated for 28 days with PBS, plain PTX (2.4 &mu;mol/kg, equivalent to 2.0 mg/kg), low-dose BPP-PTX (2.4 &mu;mol/kg, equivalent to 4.9 mg/kg), and high-dose BPP-PTX (9.6 &mu;mol/kg, equivalent to 19.6 mg/kg) every 4 days by i.p. injection. Tumor growth was assessed by measuring tumor volume every 4 days. On the fourth day of testing after the first injection, there was no significant difference in tumor volume compared with control and drug-treated groups. In the subsequent treatments, the tumors of the control mice grew significantly faster than those of mice treated with plain PTX and BPP-PTX. On day 28, mice treated with low-dose BPP-PTX showed an approximately 15% reduction in mean tumor volume compared with mice treated with plain PTX and a 54% reduction compared to controls (PBS). Meanwhile, the mean tumor volumes of mice treated with high-dose BPP-PTX were reduced by 62% compared with control animals and by approximately 30% compared to animals treated with plain PTX. Consistently, the mean tumor weight of mice with low-dose BPP-PTX treatment was 0.20 g (0.17, 0.24), which is lower than that of mice treated with plain PTX [0.26 g (0.21, 0.31)] and control mice [0.43 g (0.37, 0.49)]. The tumor weight of mice treated with high-dose BPP-PTX was significantly lower than that of the control and plain PTX-treated groups, with a mean tumor weight of only 0.16 g (0.14, 0.19). These results suggested that BPP-PTX has good tumor-suppression efficacy in vivo, even better than that of plain PTX."	"Here, we report the design, synthesis, and evaluation-in vitro and in vivo-of a novel PDC, namely BPP-PTX, whereby PTX is conjugated to one member of BPPs, Bj-BPP-9a (teprotide), via a succinyl linker. The targeting moiety was carefully selected based on previous studies. It was similarly employed with a nanoparticle carrier in vivo and was shown to modulate improved drug accumulation at the tumor site, thereby curbing tumor growth and extending the lives of tumor-bearing mice. In this study, we demonstrate for the first time that BPP-PTX functions through BPPs cognate receptor, ACE. ACE was overexpressed in TNBC cell lines but not in the receptor-positive cell line. BPP, as part of BPP-PTX, bound ACE and mediated its selective cytotoxic action through this receptor in ACE-positive TNBC cells. Furthermore, BPP-PTX demonstrated improved biodistribution, therapeutic activity, and better safety profile in vivo. These results advocate the significance of BPP-PTX as a suitable tumor-targeting PDC, strongly warranting further refinement and investigations for TNBC."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	66.73%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	2 d	0.5 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	65.31%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	Once a week for 3 weeks	0.5 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	58.77%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	6 d	0.5 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	64.57%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	8 d	0.5 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	61.33%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	10 d	0.5 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	68.27%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	12 d	0.5 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	58.76%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	14 d	0.5 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	60.43%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	16 d	0.5 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	69.20%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	20 d	0.5 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	72.90%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	2 d	1.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	67.68%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	Once a week for 3 weeks	1.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	71.16%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	6 d	1.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	72.20%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	8 d	1.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	69.39%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	10 d	1.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	77.25%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	12 d	1.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	75.40%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	14 d	1.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	72.14%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	16 d	1.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	75.49%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	20 d	1.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	67.10%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	2 d	2.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	63.36%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	Once a week for 3 weeks	2.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	70.26%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	6 d	2.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	70.04%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	8 d	2.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	72.45%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	10 d	2.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	72.98%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	12 d	2.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	78.30%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	14 d	2.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	72.91%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	16 d	2.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	73.90%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	20 d	2.0 DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	71.61%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	2 d	1.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	65.78%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	Once a week for 3 weeks	1.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	63.86%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	6 d	1.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	60.37%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	8 d	1.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	57.18%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	10 d	1.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	54.75%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	12 d	1.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	59.26%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	14 d	1.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	54.77%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	16 d	1.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	46.77%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	18 d	1.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	49.33%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	2 d	2.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	47.63%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	Once a week for 3 weeks	2.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	34.15%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	6 d	2.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	44.93%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	8 d	2.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	57.94%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	10 d	2.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	50.81%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	12 d	2.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	53.10%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	14 d	2.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	48.73%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	16 d	2.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	51.89%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	18 d	2.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	37.21%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	2 d	4.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	39.16%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	Once a week for 3 weeks	4.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	28.66%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	6 d	4.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	38.73%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	8 d	4.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	38.55%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	10 d	4.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	36.81%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	12 d	4.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	49.13%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	14 d	4.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	47.60%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	16 d	4.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	BALB/c nude mice MCF-7 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	50.36%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	18 d	4.0 mg DM1 equiv/kg	.	"We investigated the antitumor efficacy of those two PDCs on xenografted mice in vivo. LLC2B-Mal-DM1 at 1.0, 2.0 and 4.0 mg DM1 equiv./kg per week was injected into individual mice according to the tolerated concentrations of DM1 in mice: 1.0-1.5 mg/kg once per week. However, LLC2B-SS-DM1 at 0.5, 1.0, 2.0 and 4.0 mg DM1 equiv./kg was injected in the test due to its higher suppressive effect compared to LLC2B-Mal-DM in the clone formation experiment (the drug concentration used was based on the amount of the substance DM1). As shown in Figure 6A,C, LLC2B-Mal-DM1 at 2.0 and 4.0 mg DM1 equiv./kg and LLC2B-SS-DM1 with 0.5 mg DM1 equiv./kg had clear antitumor effects compared to the DM1 control groups. According to the mouse body weights, there were probably no acute life-threatening conditions in any of the groups. Moreover, the comparison of both PDCs indicated that LLC2B-SS-DM1 had a better effect than LLC2B-Mal-DM1 against the tumors."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02030	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Completely suppress concentration	0.1 &mu;g DM1 equiv./mL	&mu;g DM1 equiv./mL	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	12 h	.	Clone formation experiment	"The results show that DM1 could completely suppress the clone formation of MCF-7 cells at 0.001 &mu;g/mL, while LLC2B-SS-DM1 could completely suppress the clone formation of MCF-7 cells at 0.1 &mu;g DM1 equiv./mL. A concentration of 1 &mu;g DM1 equiv./mL was required for LLC2B-Mal-DM1 to achieve the same suppression effect."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00591	PDC_02029	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Completely suppress concentration	1 &mu;g DM1 equiv./mL	&mu;g DM1 equiv./mL	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	12 h	.	Clone formation experiment	"The results show that DM1 could completely suppress the clone formation of MCF-7 cells at 0.001 &mu;g/mL, while LLC2B-SS-DM1 could completely suppress the clone formation of MCF-7 cells at 0.1 &mu;g DM1 equiv./mL. A concentration of 1 &mu;g DM1 equiv./mL was required for LLC2B-Mal-DM1 to achieve the same suppression effect."	"A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 &deg;C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.24 &plusmn; 0.28 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	72 h	.	MTT assay	"To determine whether docetaxel or TH1902 inhibited TNBC cell proliferation, MTT assays were performed in MDA-MB-231 and HCC-70 cells exposed to various concentrations of TH19P01, docetaxel or TH1902. Inhibition of MDA-MB-231 cell proliferation was effectively triggered by both docetaxel and TH1902 compounds in a concentration-dependent manner whereas TH19P01 had no effect at the concentrations tested. The IC50 value of TH1902 was found to be comparable to that of docetaxel at low nM concentrations in both MDA-MB-231 and HCC-70 cells, which supports the rationale that conjugated docetaxel can indeed be released from TH1902 once internalized and exert its antiproliferative effect inside the targeted cancer cells. The effect of TH1902 on MBA-MB-231 cell-cycle arrest was also tested. The results show that more than 70% of treated cells were arrested in the G2/M phase of the cell cycle in comparison to vehicle-treated control cells where ~14% of the cells remained in the G2/M phase. While TH19P01 appears to be an inert peptide with no in vitro antiproliferative effects, these data confirm both the growth inhibitory effect of TH1902 and, more importantly, that the docetaxel anticancer potency was unaffected by its conjugation to the TH19P01 peptide."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1.00 &plusmn;0.55 nM	nM	.	.	.	.	Breast ductal carcinoma	HCC70 cell	1.44 h	.	72 h	.	MTT assay	"To determine whether docetaxel or TH1902 inhibited TNBC cell proliferation, MTT assays were performed in MDA-MB-231 and HCC-70 cells exposed to various concentrations of TH19P01, docetaxel or TH1902. Inhibition of MDA-MB-231 cell proliferation was effectively triggered by both docetaxel and TH1902 compounds in a concentration-dependent manner whereas TH19P01 had no effect at the concentrations tested. The IC50 value of TH1902 was found to be comparable to that of docetaxel at low nM concentrations in both MDA-MB-231 and HCC-70 cells, which supports the rationale that conjugated docetaxel can indeed be released from TH1902 once internalized and exert its antiproliferative effect inside the targeted cancer cells. The effect of TH1902 on MBA-MB-231 cell-cycle arrest was also tested. The results show that more than 70% of treated cells were arrested in the G2/M phase of the cell cycle in comparison to vehicle-treated control cells where ~14% of the cells remained in the G2/M phase. While TH19P01 appears to be an inert peptide with no in vitro antiproliferative effects, these data confirm both the growth inhibitory effect of TH1902 and, more importantly, that the docetaxel anticancer potency was unaffected by its conjugation to the TH19P01 peptide."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Apotosis rate	9.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	5 h	5 &mu;M	Flow cytometry	"The impact of docetaxel and TH1902 on MDA-MB-231 cellular morphology was evaluated and visualized by light microscopy. A drastic change in cell shape was observed in both docetaxel- and TH1902-treated cells when compared to control cells. As already reported for docetaxel-treated human renal clear cell carcinoma, MDA-MB-231 cells treated with docetaxel appeared more contracted than control cells. Interestingly, TH1902-treated cell morphology appeared even smaller, less flattened, and presented greater inter-cell spacing in comparison to those treated with free docetaxel. This observation confirms the enhanced cytotoxic effect of TH1902 when compared to docetaxel. Docetaxel is further believed to exert its cytotoxic effects through both cell cycle regulation and apoptosis induction. MDA-MB-231 cells were therefore treated for 5 or 24 hours with various concentrations of either docetaxel or TH1902, followed by AnnexinV/PI staining. TH1902 increased MDA-MB-231 cell apoptosis in a dose-dependent manner when compared to docetaxel treatment. Less than 1% apoptotic cells were measured when cells were treated with 50 &mu;M TH19P01 for 24 hours (data not shown). Overall, this suggests that, even within such a short time frame, receptor-mediated events account for the increased effects of TH1902. Finally, to confirm the role of SORT1 in TH1902 internalization and induced apoptosis, pharmacological inhibition of its apoptotic activity was measured after incubating MDA-MB-231 breast cancer cells with TH1902 in the presence or absence of the free unlabeled TH19P01 peptide or of one of the two different SORT1 ligands neurotensin or progranulin. The apoptosis assay showed that excess TH19P01 peptide, neurotensin or progranulin competitively reduced TH1902-induced cell death by 68%, 53% and 87%, respectively. This confirms the involvement of SORT1 in the internalization process of TH1902 leading to cell death in a TNBC cell model."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Apotosis rate	22.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	5 h	10 &mu;M	Flow cytometry	"The impact of docetaxel and TH1902 on MDA-MB-231 cellular morphology was evaluated and visualized by light microscopy. A drastic change in cell shape was observed in both docetaxel- and TH1902-treated cells when compared to control cells. As already reported for docetaxel-treated human renal clear cell carcinoma, MDA-MB-231 cells treated with docetaxel appeared more contracted than control cells. Interestingly, TH1902-treated cell morphology appeared even smaller, less flattened, and presented greater inter-cell spacing in comparison to those treated with free docetaxel. This observation confirms the enhanced cytotoxic effect of TH1902 when compared to docetaxel. Docetaxel is further believed to exert its cytotoxic effects through both cell cycle regulation and apoptosis induction. MDA-MB-231 cells were therefore treated for 5 or 24 hours with various concentrations of either docetaxel or TH1902, followed by AnnexinV/PI staining. TH1902 increased MDA-MB-231 cell apoptosis in a dose-dependent manner when compared to docetaxel treatment. Less than 1% apoptotic cells were measured when cells were treated with 50 &mu;M TH19P01 for 24 hours (data not shown). Overall, this suggests that, even within such a short time frame, receptor-mediated events account for the increased effects of TH1902. Finally, to confirm the role of SORT1 in TH1902 internalization and induced apoptosis, pharmacological inhibition of its apoptotic activity was measured after incubating MDA-MB-231 breast cancer cells with TH1902 in the presence or absence of the free unlabeled TH19P01 peptide or of one of the two different SORT1 ligands neurotensin or progranulin. The apoptosis assay showed that excess TH19P01 peptide, neurotensin or progranulin competitively reduced TH1902-induced cell death by 68%, 53% and 87%, respectively. This confirms the involvement of SORT1 in the internalization process of TH1902 leading to cell death in a TNBC cell model."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Apotosis rate	19.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	24 h	5 &mu;M	Flow cytometry	"The impact of docetaxel and TH1902 on MDA-MB-231 cellular morphology was evaluated and visualized by light microscopy. A drastic change in cell shape was observed in both docetaxel- and TH1902-treated cells when compared to control cells. As already reported for docetaxel-treated human renal clear cell carcinoma, MDA-MB-231 cells treated with docetaxel appeared more contracted than control cells. Interestingly, TH1902-treated cell morphology appeared even smaller, less flattened, and presented greater inter-cell spacing in comparison to those treated with free docetaxel. This observation confirms the enhanced cytotoxic effect of TH1902 when compared to docetaxel. Docetaxel is further believed to exert its cytotoxic effects through both cell cycle regulation and apoptosis induction. MDA-MB-231 cells were therefore treated for 5 or 24 hours with various concentrations of either docetaxel or TH1902, followed by AnnexinV/PI staining. TH1902 increased MDA-MB-231 cell apoptosis in a dose-dependent manner when compared to docetaxel treatment. Less than 1% apoptotic cells were measured when cells were treated with 50 &mu;M TH19P01 for 24 hours (data not shown). Overall, this suggests that, even within such a short time frame, receptor-mediated events account for the increased effects of TH1902. Finally, to confirm the role of SORT1 in TH1902 internalization and induced apoptosis, pharmacological inhibition of its apoptotic activity was measured after incubating MDA-MB-231 breast cancer cells with TH1902 in the presence or absence of the free unlabeled TH19P01 peptide or of one of the two different SORT1 ligands neurotensin or progranulin. The apoptosis assay showed that excess TH19P01 peptide, neurotensin or progranulin competitively reduced TH1902-induced cell death by 68%, 53% and 87%, respectively. This confirms the involvement of SORT1 in the internalization process of TH1902 leading to cell death in a TNBC cell model."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Apotosis rate	35.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	24 h	10 &mu;M	Flow cytometry	"The impact of docetaxel and TH1902 on MDA-MB-231 cellular morphology was evaluated and visualized by light microscopy. A drastic change in cell shape was observed in both docetaxel- and TH1902-treated cells when compared to control cells. As already reported for docetaxel-treated human renal clear cell carcinoma, MDA-MB-231 cells treated with docetaxel appeared more contracted than control cells. Interestingly, TH1902-treated cell morphology appeared even smaller, less flattened, and presented greater inter-cell spacing in comparison to those treated with free docetaxel. This observation confirms the enhanced cytotoxic effect of TH1902 when compared to docetaxel. Docetaxel is further believed to exert its cytotoxic effects through both cell cycle regulation and apoptosis induction. MDA-MB-231 cells were therefore treated for 5 or 24 hours with various concentrations of either docetaxel or TH1902, followed by AnnexinV/PI staining. TH1902 increased MDA-MB-231 cell apoptosis in a dose-dependent manner when compared to docetaxel treatment. Less than 1% apoptotic cells were measured when cells were treated with 50 &mu;M TH19P01 for 24 hours (data not shown). Overall, this suggests that, even within such a short time frame, receptor-mediated events account for the increased effects of TH1902. Finally, to confirm the role of SORT1 in TH1902 internalization and induced apoptosis, pharmacological inhibition of its apoptotic activity was measured after incubating MDA-MB-231 breast cancer cells with TH1902 in the presence or absence of the free unlabeled TH19P01 peptide or of one of the two different SORT1 ligands neurotensin or progranulin. The apoptosis assay showed that excess TH19P01 peptide, neurotensin or progranulin competitively reduced TH1902-induced cell death by 68%, 53% and 87%, respectively. This confirms the involvement of SORT1 in the internalization process of TH1902 leading to cell death in a TNBC cell model."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor growth inhibition value (TGI)	42.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	5 days	50mg /kg/wk	.	"The in vivo efficacy of TH1902 and docetaxel against a TNBC xenograft model was next investigated in vivo. Thus, nude mice were implanted in the right flank with MDA-MB-231-luc cancer cells, and luminescence was measured to monitor tumor growth. Mice were treated with intraperitoneal injections of either docetaxel at the MTD of 15 mg/kg/wk, or with TH1902 at the maximal injectable dose of 50 mg/kg/wk, both for five cycles of treatment. Unlike the vehicle-treated control group, where the average tumor luminescence increased over time, a significant decline in luminescence intensity was observed, starting at day 5 in the TH1902-treated group. The level of luminescence intensity was also significantly lower in the free docetaxel-treated group, when compared to that in the vehicle-treated control group, but remained higher than that for the TH1902-treated group. Interestingly, tumor relapse was observed in the docetaxel-treated group beginning at day 46, whereas a sustained decrease of tumor volume was maintained in the TH1902-treated group until day 74, at which time point a complete disappearance of the tumor was achieved. Representative images of luminescence are shown for vehicle-, docetaxel-, or TH1902-treated mice at day 14 when the control group reached the tumor volume endpoint and at day 74 post-treatment at the end of the experiment. Quantification of the residual tumor burden at days 14 and 74 after docetaxel or TH1902 treatment was performed, and the analysis confirmed a much better in vivo TH1902 efficacy profile than was seen with unconjugated docetaxel. Given the lack of apoptotic or antiproliferative effects of TH19P01, no rationale supports its further assessment in vivo. As TH1902 is considered a new chemical entity, its best control condition therefore is the unconjugated docetaxel molecule itself. Body weight of mice on intraperitoneal administration of either docetaxel or TH1902 remained within endpoint limits (-20%, data not shown)."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor growth inhibition value (TGI)	70.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	10 days	50mg /kg/wk	.	"The in vivo efficacy of TH1902 and docetaxel against a TNBC xenograft model was next investigated in vivo. Thus, nude mice were implanted in the right flank with MDA-MB-231-luc cancer cells, and luminescence was measured to monitor tumor growth. Mice were treated with intraperitoneal injections of either docetaxel at the MTD of 15 mg/kg/wk, or with TH1902 at the maximal injectable dose of 50 mg/kg/wk, both for five cycles of treatment. Unlike the vehicle-treated control group, where the average tumor luminescence increased over time, a significant decline in luminescence intensity was observed, starting at day 5 in the TH1902-treated group. The level of luminescence intensity was also significantly lower in the free docetaxel-treated group, when compared to that in the vehicle-treated control group, but remained higher than that for the TH1902-treated group. Interestingly, tumor relapse was observed in the docetaxel-treated group beginning at day 46, whereas a sustained decrease of tumor volume was maintained in the TH1902-treated group until day 74, at which time point a complete disappearance of the tumor was achieved. Representative images of luminescence are shown for vehicle-, docetaxel-, or TH1902-treated mice at day 14 when the control group reached the tumor volume endpoint and at day 74 post-treatment at the end of the experiment. Quantification of the residual tumor burden at days 14 and 74 after docetaxel or TH1902 treatment was performed, and the analysis confirmed a much better in vivo TH1902 efficacy profile than was seen with unconjugated docetaxel. Given the lack of apoptotic or antiproliferative effects of TH19P01, no rationale supports its further assessment in vivo. As TH1902 is considered a new chemical entity, its best control condition therefore is the unconjugated docetaxel molecule itself. Body weight of mice on intraperitoneal administration of either docetaxel or TH1902 remained within endpoint limits (-20%, data not shown)."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor growth inhibition value (TGI)	80.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	15 days	50mg /kg/wk	.	"The in vivo efficacy of TH1902 and docetaxel against a TNBC xenograft model was next investigated in vivo. Thus, nude mice were implanted in the right flank with MDA-MB-231-luc cancer cells, and luminescence was measured to monitor tumor growth. Mice were treated with intraperitoneal injections of either docetaxel at the MTD of 15 mg/kg/wk, or with TH1902 at the maximal injectable dose of 50 mg/kg/wk, both for five cycles of treatment. Unlike the vehicle-treated control group, where the average tumor luminescence increased over time, a significant decline in luminescence intensity was observed, starting at day 5 in the TH1902-treated group. The level of luminescence intensity was also significantly lower in the free docetaxel-treated group, when compared to that in the vehicle-treated control group, but remained higher than that for the TH1902-treated group. Interestingly, tumor relapse was observed in the docetaxel-treated group beginning at day 46, whereas a sustained decrease of tumor volume was maintained in the TH1902-treated group until day 74, at which time point a complete disappearance of the tumor was achieved. Representative images of luminescence are shown for vehicle-, docetaxel-, or TH1902-treated mice at day 14 when the control group reached the tumor volume endpoint and at day 74 post-treatment at the end of the experiment. Quantification of the residual tumor burden at days 14 and 74 after docetaxel or TH1902 treatment was performed, and the analysis confirmed a much better in vivo TH1902 efficacy profile than was seen with unconjugated docetaxel. Given the lack of apoptotic or antiproliferative effects of TH19P01, no rationale supports its further assessment in vivo. As TH1902 is considered a new chemical entity, its best control condition therefore is the unconjugated docetaxel molecule itself. Body weight of mice on intraperitoneal administration of either docetaxel or TH1902 remained within endpoint limits (-20%, data not shown)."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Residual tumor burden	6x10<sup>6</sup> RLU	RLU	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	14 days	50mg /kg/wk	.	"The use of intravenous administration of TH1902 was next investigated in the TNBC-derived MDA-MB-231 xenograft model. Mice subjected to docetaxel treatment were administered with three intravenous injections at 15 mg/kg/wk (MTD), whereas those treated with TH1902 received five injections of an equivalent dose of docetaxel at 35 mg/kg/wk. Similar to what was seen with the intraperitoneal administration protocol, a sustained decrease in tumor size was observed following intravenous administration of TH1902 until day 70, whereas a restart of tumor growth was observed at day 50 for the docetaxel-treated mice. When lower doses, equivalent to the quarter of the MTD, were used of docetaxel (3.75 mg/kg) and TH1902 (8.75 mg/kg), tumor growth as assessed by luminescence intensity was unaffected by intravenous administration of docetaxel, whereas it was significantly inhibited in the TH1902-treated group. This was further confirmed through the measurement of the tumor burden luminescence where TH1902 reduced it significantly in comparison to vehicle- or docetaxel-treated groups. Interestingly, body weight changes remained within endpoint limits in mice on intravenous administration of either docetaxel or TH1902 (data not shown). Similar conclusions were reached on testing another TNBC-derived HCC-70 xenograft model. In fact, administration of TH1902 at 8.75 mg/kg/wk led to a 93% inhibition of HCC-70 tumor growth as compared to 24% for docetaxel alone at an equivalent dose."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor growth inhibition value (TGI)	55.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	5 days	35 mg/kg/wk	.	"The use of intravenous administration of TH1902 was next investigated in the TNBC-derived MDA-MB-231 xenograft model. Mice subjected to docetaxel treatment were administered with three intravenous injections at 15 mg/kg/wk (MTD), whereas those treated with TH1902 received five injections of an equivalent dose of docetaxel at 35 mg/kg/wk. Similar to what was seen with the intraperitoneal administration protocol, a sustained decrease in tumor size was observed following intravenous administration of TH1902 until day 70, whereas a restart of tumor growth was observed at day 50 for the docetaxel-treated mice. When lower doses, equivalent to the quarter of the MTD, were used of docetaxel (3.75 mg/kg) and TH1902 (8.75 mg/kg), tumor growth as assessed by luminescence intensity was unaffected by intravenous administration of docetaxel, whereas it was significantly inhibited in the TH1902-treated group. This was further confirmed through the measurement of the tumor burden luminescence where TH1902 reduced it significantly in comparison to vehicle- or docetaxel-treated groups. Interestingly, body weight changes remained within endpoint limits in mice on intravenous administration of either docetaxel or TH1902 (data not shown). Similar conclusions were reached on testing another TNBC-derived HCC-70 xenograft model. In fact, administration of TH1902 at 8.75 mg/kg/wk led to a 93% inhibition of HCC-70 tumor growth as compared to 24% for docetaxel alone at an equivalent dose."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor growth inhibition value (TGI)	80.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	10 days	35 mg/kg/wk	.	"The use of intravenous administration of TH1902 was next investigated in the TNBC-derived MDA-MB-231 xenograft model. Mice subjected to docetaxel treatment were administered with three intravenous injections at 15 mg/kg/wk (MTD), whereas those treated with TH1902 received five injections of an equivalent dose of docetaxel at 35 mg/kg/wk. Similar to what was seen with the intraperitoneal administration protocol, a sustained decrease in tumor size was observed following intravenous administration of TH1902 until day 70, whereas a restart of tumor growth was observed at day 50 for the docetaxel-treated mice. When lower doses, equivalent to the quarter of the MTD, were used of docetaxel (3.75 mg/kg) and TH1902 (8.75 mg/kg), tumor growth as assessed by luminescence intensity was unaffected by intravenous administration of docetaxel, whereas it was significantly inhibited in the TH1902-treated group. This was further confirmed through the measurement of the tumor burden luminescence where TH1902 reduced it significantly in comparison to vehicle- or docetaxel-treated groups. Interestingly, body weight changes remained within endpoint limits in mice on intravenous administration of either docetaxel or TH1902 (data not shown). Similar conclusions were reached on testing another TNBC-derived HCC-70 xenograft model. In fact, administration of TH1902 at 8.75 mg/kg/wk led to a 93% inhibition of HCC-70 tumor growth as compared to 24% for docetaxel alone at an equivalent dose."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor growth inhibition value (TGI)	86.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	15 days	35 mg/kg/wk	.	"The use of intravenous administration of TH1902 was next investigated in the TNBC-derived MDA-MB-231 xenograft model. Mice subjected to docetaxel treatment were administered with three intravenous injections at 15 mg/kg/wk (MTD), whereas those treated with TH1902 received five injections of an equivalent dose of docetaxel at 35 mg/kg/wk. Similar to what was seen with the intraperitoneal administration protocol, a sustained decrease in tumor size was observed following intravenous administration of TH1902 until day 70, whereas a restart of tumor growth was observed at day 50 for the docetaxel-treated mice. When lower doses, equivalent to the quarter of the MTD, were used of docetaxel (3.75 mg/kg) and TH1902 (8.75 mg/kg), tumor growth as assessed by luminescence intensity was unaffected by intravenous administration of docetaxel, whereas it was significantly inhibited in the TH1902-treated group. This was further confirmed through the measurement of the tumor burden luminescence where TH1902 reduced it significantly in comparison to vehicle- or docetaxel-treated groups. Interestingly, body weight changes remained within endpoint limits in mice on intravenous administration of either docetaxel or TH1902 (data not shown). Similar conclusions were reached on testing another TNBC-derived HCC-70 xenograft model. In fact, administration of TH1902 at 8.75 mg/kg/wk led to a 93% inhibition of HCC-70 tumor growth as compared to 24% for docetaxel alone at an equivalent dose."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor growth inhibition value (TGI)	91.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	20 days	35 mg/kg/wk	.	"The use of intravenous administration of TH1902 was next investigated in the TNBC-derived MDA-MB-231 xenograft model. Mice subjected to docetaxel treatment were administered with three intravenous injections at 15 mg/kg/wk (MTD), whereas those treated with TH1902 received five injections of an equivalent dose of docetaxel at 35 mg/kg/wk. Similar to what was seen with the intraperitoneal administration protocol, a sustained decrease in tumor size was observed following intravenous administration of TH1902 until day 70, whereas a restart of tumor growth was observed at day 50 for the docetaxel-treated mice. When lower doses, equivalent to the quarter of the MTD, were used of docetaxel (3.75 mg/kg) and TH1902 (8.75 mg/kg), tumor growth as assessed by luminescence intensity was unaffected by intravenous administration of docetaxel, whereas it was significantly inhibited in the TH1902-treated group. This was further confirmed through the measurement of the tumor burden luminescence where TH1902 reduced it significantly in comparison to vehicle- or docetaxel-treated groups. Interestingly, body weight changes remained within endpoint limits in mice on intravenous administration of either docetaxel or TH1902 (data not shown). Similar conclusions were reached on testing another TNBC-derived HCC-70 xenograft model. In fact, administration of TH1902 at 8.75 mg/kg/wk led to a 93% inhibition of HCC-70 tumor growth as compared to 24% for docetaxel alone at an equivalent dose."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor growth inhibition value (TGI)	33.30%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	5 days	8.75 mg/kg	.	"The use of intravenous administration of TH1902 was next investigated in the TNBC-derived MDA-MB-231 xenograft model. Mice subjected to docetaxel treatment were administered with three intravenous injections at 15 mg/kg/wk (MTD), whereas those treated with TH1902 received five injections of an equivalent dose of docetaxel at 35 mg/kg/wk. Similar to what was seen with the intraperitoneal administration protocol, a sustained decrease in tumor size was observed following intravenous administration of TH1902 until day 70, whereas a restart of tumor growth was observed at day 50 for the docetaxel-treated mice. When lower doses, equivalent to the quarter of the MTD, were used of docetaxel (3.75 mg/kg) and TH1902 (8.75 mg/kg), tumor growth as assessed by luminescence intensity was unaffected by intravenous administration of docetaxel, whereas it was significantly inhibited in the TH1902-treated group. This was further confirmed through the measurement of the tumor burden luminescence where TH1902 reduced it significantly in comparison to vehicle- or docetaxel-treated groups. Interestingly, body weight changes remained within endpoint limits in mice on intravenous administration of either docetaxel or TH1902 (data not shown). Similar conclusions were reached on testing another TNBC-derived HCC-70 xenograft model. In fact, administration of TH1902 at 8.75 mg/kg/wk led to a 93% inhibition of HCC-70 tumor growth as compared to 24% for docetaxel alone at an equivalent dose."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor growth inhibition value (TGI)	50.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	10 days	8.75 mg/kg	.	"The use of intravenous administration of TH1902 was next investigated in the TNBC-derived MDA-MB-231 xenograft model. Mice subjected to docetaxel treatment were administered with three intravenous injections at 15 mg/kg/wk (MTD), whereas those treated with TH1902 received five injections of an equivalent dose of docetaxel at 35 mg/kg/wk. Similar to what was seen with the intraperitoneal administration protocol, a sustained decrease in tumor size was observed following intravenous administration of TH1902 until day 70, whereas a restart of tumor growth was observed at day 50 for the docetaxel-treated mice. When lower doses, equivalent to the quarter of the MTD, were used of docetaxel (3.75 mg/kg) and TH1902 (8.75 mg/kg), tumor growth as assessed by luminescence intensity was unaffected by intravenous administration of docetaxel, whereas it was significantly inhibited in the TH1902-treated group. This was further confirmed through the measurement of the tumor burden luminescence where TH1902 reduced it significantly in comparison to vehicle- or docetaxel-treated groups. Interestingly, body weight changes remained within endpoint limits in mice on intravenous administration of either docetaxel or TH1902 (data not shown). Similar conclusions were reached on testing another TNBC-derived HCC-70 xenograft model. In fact, administration of TH1902 at 8.75 mg/kg/wk led to a 93% inhibition of HCC-70 tumor growth as compared to 24% for docetaxel alone at an equivalent dose."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor growth inhibition value (TGI)	66.70%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	15 days	8.75 mg/kg	.	"The use of intravenous administration of TH1902 was next investigated in the TNBC-derived MDA-MB-231 xenograft model. Mice subjected to docetaxel treatment were administered with three intravenous injections at 15 mg/kg/wk (MTD), whereas those treated with TH1902 received five injections of an equivalent dose of docetaxel at 35 mg/kg/wk. Similar to what was seen with the intraperitoneal administration protocol, a sustained decrease in tumor size was observed following intravenous administration of TH1902 until day 70, whereas a restart of tumor growth was observed at day 50 for the docetaxel-treated mice. When lower doses, equivalent to the quarter of the MTD, were used of docetaxel (3.75 mg/kg) and TH1902 (8.75 mg/kg), tumor growth as assessed by luminescence intensity was unaffected by intravenous administration of docetaxel, whereas it was significantly inhibited in the TH1902-treated group. This was further confirmed through the measurement of the tumor burden luminescence where TH1902 reduced it significantly in comparison to vehicle- or docetaxel-treated groups. Interestingly, body weight changes remained within endpoint limits in mice on intravenous administration of either docetaxel or TH1902 (data not shown). Similar conclusions were reached on testing another TNBC-derived HCC-70 xenograft model. In fact, administration of TH1902 at 8.75 mg/kg/wk led to a 93% inhibition of HCC-70 tumor growth as compared to 24% for docetaxel alone at an equivalent dose."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Tumor growth inhibition value (TGI)	80.00%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	20 days	8.75 mg/kg	.	"The use of intravenous administration of TH1902 was next investigated in the TNBC-derived MDA-MB-231 xenograft model. Mice subjected to docetaxel treatment were administered with three intravenous injections at 15 mg/kg/wk (MTD), whereas those treated with TH1902 received five injections of an equivalent dose of docetaxel at 35 mg/kg/wk. Similar to what was seen with the intraperitoneal administration protocol, a sustained decrease in tumor size was observed following intravenous administration of TH1902 until day 70, whereas a restart of tumor growth was observed at day 50 for the docetaxel-treated mice. When lower doses, equivalent to the quarter of the MTD, were used of docetaxel (3.75 mg/kg) and TH1902 (8.75 mg/kg), tumor growth as assessed by luminescence intensity was unaffected by intravenous administration of docetaxel, whereas it was significantly inhibited in the TH1902-treated group. This was further confirmed through the measurement of the tumor burden luminescence where TH1902 reduced it significantly in comparison to vehicle- or docetaxel-treated groups. Interestingly, body weight changes remained within endpoint limits in mice on intravenous administration of either docetaxel or TH1902 (data not shown). Similar conclusions were reached on testing another TNBC-derived HCC-70 xenograft model. In fact, administration of TH1902 at 8.75 mg/kg/wk led to a 93% inhibition of HCC-70 tumor growth as compared to 24% for docetaxel alone at an equivalent dose."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00590	PDC_00349	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Residual tumor burden	2x10<sup>6</sup> RLU	RLU	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.44 h	.	27 days	35 mg/kg	.	"The use of intravenous administration of TH1902 was next investigated in the TNBC-derived MDA-MB-231 xenograft model. Mice subjected to docetaxel treatment were administered with three intravenous injections at 15 mg/kg/wk (MTD), whereas those treated with TH1902 received five injections of an equivalent dose of docetaxel at 35 mg/kg/wk. Similar to what was seen with the intraperitoneal administration protocol, a sustained decrease in tumor size was observed following intravenous administration of TH1902 until day 70, whereas a restart of tumor growth was observed at day 50 for the docetaxel-treated mice. When lower doses, equivalent to the quarter of the MTD, were used of docetaxel (3.75 mg/kg) and TH1902 (8.75 mg/kg), tumor growth as assessed by luminescence intensity was unaffected by intravenous administration of docetaxel, whereas it was significantly inhibited in the TH1902-treated group. This was further confirmed through the measurement of the tumor burden luminescence where TH1902 reduced it significantly in comparison to vehicle- or docetaxel-treated groups. Interestingly, body weight changes remained within endpoint limits in mice on intravenous administration of either docetaxel or TH1902 (data not shown). Similar conclusions were reached on testing another TNBC-derived HCC-70 xenograft model. In fact, administration of TH1902 at 8.75 mg/kg/wk led to a 93% inhibition of HCC-70 tumor growth as compared to 24% for docetaxel alone at an equivalent dose."	"Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel."
REF00589	PDC_02031	Prostate carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	177.4 &plusmn; 10.2 nM	nM	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02032	Prostate carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	181.4 &plusmn; 8.7 nM	nM	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	1.013 h	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02033	Prostate carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	202.2 &plusmn; 7.9 nM	nM	.	.	.	.	Prostate carcinoma	LNCaP C4-2 cell	.	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02031	Prostate carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	208.7 &plusmn; 8.7 nM	nM	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02032	Prostate carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	611.2 &plusmn; 18.4 nM	nM	.	.	.	.	Prostate carcinoma	DU145 cell	1.013 h	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02033	Prostate carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	751.1 &plusmn; 27.2 nM	nM	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02031	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	205.3 &plusmn; 18.7 nM	nM	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02032	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	160.4 &plusmn; 8.4 nM	nM	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	1.013 h	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02033	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	162.4 &plusmn; 3.2 nM	nM	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02031	Breast adenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	277.3 &plusmn; 14.5 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02032	Breast adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	251.6 &plusmn; 17.6 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	1.013 h	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02033	Breast adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	235 &plusmn; 11.4 nM	nM	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02031	.	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	106 &plusmn; 8.3 nM	nM	.	.	.	.	Normal	HEK293 cell	.	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02032	.	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	534.5 &plusmn; 23.3 nM	nM	.	.	.	.	Normal	HEK293 cell	1.013 h	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00589	PDC_02033	.	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	483.3 &plusmn; 17.2 nM	nM	.	.	.	.	Normal	HEK293 cell	.	.	72 h	.	MTS assay	"The conjugates therapeutic efficacy with targeting moieties was evaluated using prostate cancer cell lines with and without EDB-Fn overexpression (C4-2 and DU-145). Breast cancer cell lines with and without integrin v1 overexpression (MCF-7 and MDA-MB-231) were also used to evaluate antiproliferative activity. Noncancerous embryonic kidney epithelial cell line (HEK-293) was used as a control since this cell line did not express both biomarkers. All the compounds with and without targeting moieties showed comparable or lower antiproliferative activity than the CBT alone after 72 h incubation. The antiproliferative activity of compound 11 on MCF-7 (IC50 = 160.4 nM) was 1.6 times greater than on MDA-MB-231 (IC50 = 251.6 nM), showing a slight improvement in antiproliferative activity. A similar observation was found with compound 16 that showed 1.45 times higher antiproliferative activity on MCF-7 (IC50 = 162.4 nM) as compared to MDA-MB-231 cells (IC50 = 235.0 nM). Both MCF-7 and MDA-MB-231 are breast cancer cell lines. MDA-MB-231 is triple-negative breast cancer cells, and it showed higher IC50 values for CBT than MCF-7 cells. Later, the antiproliferative activity was compared between MCF-7 and the control cells (HEK-293); it was observed that compound 11 showed 3.33 times higher antiproliferative activity on MCF-7 cells (IC50 for 11 = 160.4 nM) compared to HEK-293 (IC50 for 11 = 534.5 nM), and compound 16 showed 4.6 times higher antiproliferative activity on MCF-7 (IC50 for 16 = 162.4 nM) compared to HEK-293 (IC50 for 16 = 483.3 nM). Thereafter, we wanted to assess the effectiveness of the EDB-Fn targeting moiety by comparing the antiproliferative activities on prostate cancer cell lines with and without EDB-Fn overexpression. The data showed a similar trend to that observed in breast cancer cells. For instance, compound 11 showed 3.4 times higher antiproliferative activity on C4-2 (IC50 for 11 = 181.4 nM) compared to DU-145 (IC50 for 11 = 611.2 nM). Similarly, compound 16 showed 3.7 times higher antiproliferative activity on C4-2 (IC50 for 16 = 202.2 nM) compared to DU-145 (IC50 for 16 = 751.1 nM). Compound 16 (possessing EDB-Fn targeting moiety) showed 1.1 times less antiproliferative activity compared to compound 6 (cCPP-CBT, without targeting moiety) on C4-2 cell lines, but compound 16 showed a much higher difference (3.6 times) in antiproliferative activity when compared with compound 6 on EDB-Fn moderately expressing DU-145 cell line. This data is further corroborated in EDB-Fn nonexpressing HEK-293. For instance, compound 16 showed 4.6 times less antiproliferative activity when compared with compound 6 on HEK-293 cell line. It can be inferred from the data (Table 2) that the EDB-Fn targeting conjugate was significantly effective on EDB-Fn overexpressing cells, while the conjugate has minimal effect on nonexpressing or moderately expressing cells. In conclusion, it is plausible to state that the presence of conjugating moieties on compound 11 (integrin targeting) and compound 16 (EDB-Fn targeting) significantly affects their ability to adhere and deliver the chemotherapeutic agent selectively to biomarker overexpressing cancer cells."	"The present study explores two different targeting peptides (TPs), RGDC (TP1), and CTVRTSAD (TP2), toward av&beta;1 integrin and EDB-Fn, respectively. TP1 or TP2 is covalently conjugated via disulfide bond to [C(WR)2K(WR)2]-(CBT) (6) to provide CBT conjugates (11, 16) containing an active targeting ability with increased aqueous solubility without decreasing cellular uptake. Targeting peptides may enable cCPP-CBT to target biomarker overexpressing tumor cells, and cCPP can assist in improving the physicochemical properties of CBT and delivery into the cancer cells. The conjugates in vitro stability was examined in various relevant conditions to mimic the cancerous versus normal physiological environment. Conjugates were evaluated in human plasma at two different glutathione concentrations (GSH, 1 mM and 10 mM) and two different pHs (6.5 and 7.4). The reported GSH level in noncancerous conditions is below 1 mM and approximately 10 mM at the cancer site. The in vitro antiproliferative assay using a biomarker overexpressing cell lines was compared to those without or with moderately expressing cancer cell lines. The study results demonstrate that targeting enhances the efficacy of CBT on cancer cell lines overexpressing extracellular biomarkers."
REF00588	PDC_02034	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	3.5 &mu;M	&mu;M	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	24 h	.	CCK-8 assay	"Murine melanoma cells (B16-F10) were chosen as the object for evaluating the cytotoxicity of the seven glycolipid peptides and R-C12 by the CCK-8 assay. Based on our previous study, the HEK-293T cell line was also chosen as the noncancer cell line to evaluate the selectivity of glycolipid peptides. IC50 represents the concentration of glycolipid peptides and R-C12 that induce 50% cell death. As shown in Figure 1A, modification of the glucose derivative at different sites of R-C12 results in different cytotoxicity profiles. According to the IC50 values, for B16-F10 cells, the cytotoxic activity of peptides was arranged as follows R-C12-4 > R-C12-1 &asymp; R-C12-2 &asymp; R-C12-3 &asymp; R-C12 > R-C12-5 > R-C12-6 > R-C12-7, in which R-C12-4 demonstrated the highest cytotoxicity on B16-F10 cells (IC50 = 1.9 &mu;M)"	"In this study, we would investigate the co-modification of fatty acids and monosaccharides in anticancer peptides, as we expect to optimize the selectivity and cytotoxicity of the peptide at the same time. Based on our previous study, the lipopeptide R-C12 was selected as a template to perform glucose derivative modification at different positions as we supposed that the glucose derivative modification position in R-C12 might be a crucial factor in its selectivity and activity optimization. The glucose derivative was covalently coupled to different sites in R-C12 through its -amino group of a Lys residue, which was obtained by replacing the Arg residue. R-C12 contains seven Arg residues, accordingly, seven glycolipid peptides were designed and synthesized, which were named R-C12-1, R-C12-2, R-C12-3, R-C12-4, R-C12-5, R-C12-6, and R-C12-7. Various physiochemical properties including the hydrodynamic size, &zeta;-potential, secondary structure, and hydrophobicity were determined to explain the different cytotoxicity and selectivity of these glycolipid peptides. On the other hand, the strength of the binding between glycolipid peptides and the cancer cells mediated by GLUT1 has also been explored. The most optimized glycolipid peptide R-C12-4 demonstrated significant cytotoxicity and antimetastasis in vitro and in vivo, which indicated that it may be a good lead for anticancer drug development."
REF00588	PDC_02035	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	3.3 &mu;M	&mu;M	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	24 h	.	CCK-8 assay	"Murine melanoma cells (B16-F10) were chosen as the object for evaluating the cytotoxicity of the seven glycolipid peptides and R-C12 by the CCK-8 assay. Based on our previous study, the HEK-293T cell line was also chosen as the noncancer cell line to evaluate the selectivity of glycolipid peptides. IC50 represents the concentration of glycolipid peptides and R-C12 that induce 50% cell death. As shown in Figure 1A, modification of the glucose derivative at different sites of R-C12 results in different cytotoxicity profiles. According to the IC50 values, for B16-F10 cells, the cytotoxic activity of peptides was arranged as follows R-C12-4 > R-C12-1 &asymp; R-C12-2 &asymp; R-C12-3 &asymp; R-C12 > R-C12-5 > R-C12-6 > R-C12-7, in which R-C12-4 demonstrated the highest cytotoxicity on B16-F10 cells (IC50 = 1.9 &mu;M)"	"In this study, we would investigate the co-modification of fatty acids and monosaccharides in anticancer peptides, as we expect to optimize the selectivity and cytotoxicity of the peptide at the same time. Based on our previous study, the lipopeptide R-C12 was selected as a template to perform glucose derivative modification at different positions as we supposed that the glucose derivative modification position in R-C12 might be a crucial factor in its selectivity and activity optimization. The glucose derivative was covalently coupled to different sites in R-C12 through its -amino group of a Lys residue, which was obtained by replacing the Arg residue. R-C12 contains seven Arg residues, accordingly, seven glycolipid peptides were designed and synthesized, which were named R-C12-1, R-C12-2, R-C12-3, R-C12-4, R-C12-5, R-C12-6, and R-C12-7. Various physiochemical properties including the hydrodynamic size, &zeta;-potential, secondary structure, and hydrophobicity were determined to explain the different cytotoxicity and selectivity of these glycolipid peptides. On the other hand, the strength of the binding between glycolipid peptides and the cancer cells mediated by GLUT1 has also been explored. The most optimized glycolipid peptide R-C12-4 demonstrated significant cytotoxicity and antimetastasis in vitro and in vivo, which indicated that it may be a good lead for anticancer drug development."
REF00588	PDC_02036	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	3.8 &mu;M	&mu;M	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	24 h	.	CCK-8 assay	"Murine melanoma cells (B16-F10) were chosen as the object for evaluating the cytotoxicity of the seven glycolipid peptides and R-C12 by the CCK-8 assay. Based on our previous study, the HEK-293T cell line was also chosen as the noncancer cell line to evaluate the selectivity of glycolipid peptides. IC50 represents the concentration of glycolipid peptides and R-C12 that induce 50% cell death. As shown in Figure 1A, modification of the glucose derivative at different sites of R-C12 results in different cytotoxicity profiles. According to the IC50 values, for B16-F10 cells, the cytotoxic activity of peptides was arranged as follows R-C12-4 > R-C12-1 &asymp; R-C12-2 &asymp; R-C12-3 &asymp; R-C12 > R-C12-5 > R-C12-6 > R-C12-7, in which R-C12-4 demonstrated the highest cytotoxicity on B16-F10 cells (IC50 = 1.9 &mu;M)"	"In this study, we would investigate the co-modification of fatty acids and monosaccharides in anticancer peptides, as we expect to optimize the selectivity and cytotoxicity of the peptide at the same time. Based on our previous study, the lipopeptide R-C12 was selected as a template to perform glucose derivative modification at different positions as we supposed that the glucose derivative modification position in R-C12 might be a crucial factor in its selectivity and activity optimization. The glucose derivative was covalently coupled to different sites in R-C12 through its -amino group of a Lys residue, which was obtained by replacing the Arg residue. R-C12 contains seven Arg residues, accordingly, seven glycolipid peptides were designed and synthesized, which were named R-C12-1, R-C12-2, R-C12-3, R-C12-4, R-C12-5, R-C12-6, and R-C12-7. Various physiochemical properties including the hydrodynamic size, &zeta;-potential, secondary structure, and hydrophobicity were determined to explain the different cytotoxicity and selectivity of these glycolipid peptides. On the other hand, the strength of the binding between glycolipid peptides and the cancer cells mediated by GLUT1 has also been explored. The most optimized glycolipid peptide R-C12-4 demonstrated significant cytotoxicity and antimetastasis in vitro and in vivo, which indicated that it may be a good lead for anticancer drug development."
REF00588	PDC_02037	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1.9 &mu;M	&mu;M	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	24 h	.	CCK-8 assay	"Murine melanoma cells (B16-F10) were chosen as the object for evaluating the cytotoxicity of the seven glycolipid peptides and R-C12 by the CCK-8 assay. Based on our previous study, the HEK-293T cell line was also chosen as the noncancer cell line to evaluate the selectivity of glycolipid peptides. IC50 represents the concentration of glycolipid peptides and R-C12 that induce 50% cell death. As shown in Figure 1A, modification of the glucose derivative at different sites of R-C12 results in different cytotoxicity profiles. According to the IC50 values, for B16-F10 cells, the cytotoxic activity of peptides was arranged as follows R-C12-4 > R-C12-1 &asymp; R-C12-2 &asymp; R-C12-3 &asymp; R-C12 > R-C12-5 > R-C12-6 > R-C12-7, in which R-C12-4 demonstrated the highest cytotoxicity on B16-F10 cells (IC50 = 1.9 &mu;M)"	"In this study, we would investigate the co-modification of fatty acids and monosaccharides in anticancer peptides, as we expect to optimize the selectivity and cytotoxicity of the peptide at the same time. Based on our previous study, the lipopeptide R-C12 was selected as a template to perform glucose derivative modification at different positions as we supposed that the glucose derivative modification position in R-C12 might be a crucial factor in its selectivity and activity optimization. The glucose derivative was covalently coupled to different sites in R-C12 through its -amino group of a Lys residue, which was obtained by replacing the Arg residue. R-C12 contains seven Arg residues, accordingly, seven glycolipid peptides were designed and synthesized, which were named R-C12-1, R-C12-2, R-C12-3, R-C12-4, R-C12-5, R-C12-6, and R-C12-7. Various physiochemical properties including the hydrodynamic size, &zeta;-potential, secondary structure, and hydrophobicity were determined to explain the different cytotoxicity and selectivity of these glycolipid peptides. On the other hand, the strength of the binding between glycolipid peptides and the cancer cells mediated by GLUT1 has also been explored. The most optimized glycolipid peptide R-C12-4 demonstrated significant cytotoxicity and antimetastasis in vitro and in vivo, which indicated that it may be a good lead for anticancer drug development."
REF00588	PDC_02038	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	4.1 &mu;M	&mu;M	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	24 h	.	CCK-8 assay	"Murine melanoma cells (B16-F10) were chosen as the object for evaluating the cytotoxicity of the seven glycolipid peptides and R-C12 by the CCK-8 assay. Based on our previous study, the HEK-293T cell line was also chosen as the noncancer cell line to evaluate the selectivity of glycolipid peptides. IC50 represents the concentration of glycolipid peptides and R-C12 that induce 50% cell death. As shown in Figure 1A, modification of the glucose derivative at different sites of R-C12 results in different cytotoxicity profiles. According to the IC50 values, for B16-F10 cells, the cytotoxic activity of peptides was arranged as follows R-C12-4 > R-C12-1 &asymp; R-C12-2 &asymp; R-C12-3 &asymp; R-C12 > R-C12-5 > R-C12-6 > R-C12-7, in which R-C12-4 demonstrated the highest cytotoxicity on B16-F10 cells (IC50 = 1.9 &mu;M)"	"In this study, we would investigate the co-modification of fatty acids and monosaccharides in anticancer peptides, as we expect to optimize the selectivity and cytotoxicity of the peptide at the same time. Based on our previous study, the lipopeptide R-C12 was selected as a template to perform glucose derivative modification at different positions as we supposed that the glucose derivative modification position in R-C12 might be a crucial factor in its selectivity and activity optimization. The glucose derivative was covalently coupled to different sites in R-C12 through its -amino group of a Lys residue, which was obtained by replacing the Arg residue. R-C12 contains seven Arg residues, accordingly, seven glycolipid peptides were designed and synthesized, which were named R-C12-1, R-C12-2, R-C12-3, R-C12-4, R-C12-5, R-C12-6, and R-C12-7. Various physiochemical properties including the hydrodynamic size, &zeta;-potential, secondary structure, and hydrophobicity were determined to explain the different cytotoxicity and selectivity of these glycolipid peptides. On the other hand, the strength of the binding between glycolipid peptides and the cancer cells mediated by GLUT1 has also been explored. The most optimized glycolipid peptide R-C12-4 demonstrated significant cytotoxicity and antimetastasis in vitro and in vivo, which indicated that it may be a good lead for anticancer drug development."
REF00588	PDC_02039	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	5.3 &mu;M	&mu;M	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	24 h	.	CCK-8 assay	"Murine melanoma cells (B16-F10) were chosen as the object for evaluating the cytotoxicity of the seven glycolipid peptides and R-C12 by the CCK-8 assay. Based on our previous study, the HEK-293T cell line was also chosen as the noncancer cell line to evaluate the selectivity of glycolipid peptides. IC50 represents the concentration of glycolipid peptides and R-C12 that induce 50% cell death. As shown in Figure 1A, modification of the glucose derivative at different sites of R-C12 results in different cytotoxicity profiles. According to the IC50 values, for B16-F10 cells, the cytotoxic activity of peptides was arranged as follows R-C12-4 > R-C12-1 &asymp; R-C12-2 &asymp; R-C12-3 &asymp; R-C12 > R-C12-5 > R-C12-6 > R-C12-7, in which R-C12-4 demonstrated the highest cytotoxicity on B16-F10 cells (IC50 = 1.9 &mu;M)"	"In this study, we would investigate the co-modification of fatty acids and monosaccharides in anticancer peptides, as we expect to optimize the selectivity and cytotoxicity of the peptide at the same time. Based on our previous study, the lipopeptide R-C12 was selected as a template to perform glucose derivative modification at different positions as we supposed that the glucose derivative modification position in R-C12 might be a crucial factor in its selectivity and activity optimization. The glucose derivative was covalently coupled to different sites in R-C12 through its -amino group of a Lys residue, which was obtained by replacing the Arg residue. R-C12 contains seven Arg residues, accordingly, seven glycolipid peptides were designed and synthesized, which were named R-C12-1, R-C12-2, R-C12-3, R-C12-4, R-C12-5, R-C12-6, and R-C12-7. Various physiochemical properties including the hydrodynamic size, &zeta;-potential, secondary structure, and hydrophobicity were determined to explain the different cytotoxicity and selectivity of these glycolipid peptides. On the other hand, the strength of the binding between glycolipid peptides and the cancer cells mediated by GLUT1 has also been explored. The most optimized glycolipid peptide R-C12-4 demonstrated significant cytotoxicity and antimetastasis in vitro and in vivo, which indicated that it may be a good lead for anticancer drug development."
REF00588	PDC_02040	Melanoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	7.2 &mu;M	&mu;M	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	24 h	.	CCK-8 assay	"Murine melanoma cells (B16-F10) were chosen as the object for evaluating the cytotoxicity of the seven glycolipid peptides and R-C12 by the CCK-8 assay. Based on our previous study, the HEK-293T cell line was also chosen as the noncancer cell line to evaluate the selectivity of glycolipid peptides. IC50 represents the concentration of glycolipid peptides and R-C12 that induce 50% cell death. As shown in Figure 1A, modification of the glucose derivative at different sites of R-C12 results in different cytotoxicity profiles. According to the IC50 values, for B16-F10 cells, the cytotoxic activity of peptides was arranged as follows R-C12-4 > R-C12-1 &asymp; R-C12-2 &asymp; R-C12-3 &asymp; R-C12 > R-C12-5 > R-C12-6 > R-C12-7, in which R-C12-4 demonstrated the highest cytotoxicity on B16-F10 cells (IC50 = 1.9 &mu;M)"	"In this study, we would investigate the co-modification of fatty acids and monosaccharides in anticancer peptides, as we expect to optimize the selectivity and cytotoxicity of the peptide at the same time. Based on our previous study, the lipopeptide R-C12 was selected as a template to perform glucose derivative modification at different positions as we supposed that the glucose derivative modification position in R-C12 might be a crucial factor in its selectivity and activity optimization. The glucose derivative was covalently coupled to different sites in R-C12 through its -amino group of a Lys residue, which was obtained by replacing the Arg residue. R-C12 contains seven Arg residues, accordingly, seven glycolipid peptides were designed and synthesized, which were named R-C12-1, R-C12-2, R-C12-3, R-C12-4, R-C12-5, R-C12-6, and R-C12-7. Various physiochemical properties including the hydrodynamic size, &zeta;-potential, secondary structure, and hydrophobicity were determined to explain the different cytotoxicity and selectivity of these glycolipid peptides. On the other hand, the strength of the binding between glycolipid peptides and the cancer cells mediated by GLUT1 has also been explored. The most optimized glycolipid peptide R-C12-4 demonstrated significant cytotoxicity and antimetastasis in vitro and in vivo, which indicated that it may be a good lead for anticancer drug development."
REF00588	PDC_02037	Melanoma	KM mice B16-F10 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	50.00%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	3 days	200 &mu;L 15 mg/kg	.	"For the subcutaneous transplantation model, R-C12 or R-C12-4 was injected intraperitoneally every other day at the dose of 15 mg/kg. As shown in Figure 7A,B, after 12 days, R-C12-4 and R-C12 have a significant inhibition effect on the BALB/c mice tumor volume compared to the control group (p < 0.01 and p < 0.05, respectively). For the metastasis model, R-C12 or R-C12-4 was applied by the tail intravenous injection every 2 days at the dose of 10 mg/kg. As shown in Figure 7D, significantly fewer metastatic nodules from the lungs of Kunming (KM) mice were observed in the R-C12-4 and R-C12 treatment groups compared to the control and this result was confirmed by the H&E staining of lung sections. Visible tumor nodules were counted on the surface of the lung demonstrating a significant difference between the control and R-C12 and R-C12-4 treatment groups (p < 0.05). It is noteworthy that both R-C12 and R-C12-4 did not affect the mouse body weight either in the subcutaneous transplantation model or in the metastasis model, indicating that these peptides did not diminish their overall health."	"In this study, we would investigate the co-modification of fatty acids and monosaccharides in anticancer peptides, as we expect to optimize the selectivity and cytotoxicity of the peptide at the same time. Based on our previous study, the lipopeptide R-C12 was selected as a template to perform glucose derivative modification at different positions as we supposed that the glucose derivative modification position in R-C12 might be a crucial factor in its selectivity and activity optimization. The glucose derivative was covalently coupled to different sites in R-C12 through its -amino group of a Lys residue, which was obtained by replacing the Arg residue. R-C12 contains seven Arg residues, accordingly, seven glycolipid peptides were designed and synthesized, which were named R-C12-1, R-C12-2, R-C12-3, R-C12-4, R-C12-5, R-C12-6, and R-C12-7. Various physiochemical properties including the hydrodynamic size, &zeta;-potential, secondary structure, and hydrophobicity were determined to explain the different cytotoxicity and selectivity of these glycolipid peptides. On the other hand, the strength of the binding between glycolipid peptides and the cancer cells mediated by GLUT1 has also been explored. The most optimized glycolipid peptide R-C12-4 demonstrated significant cytotoxicity and antimetastasis in vitro and in vivo, which indicated that it may be a good lead for anticancer drug development."
REF00588	PDC_02037	Melanoma	BALB/c mice B16-F10 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	38.00%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	6 days	200 &mu;L 15 mg/kg	.	"For the subcutaneous transplantation model, R-C12 or R-C12-4 was injected intraperitoneally every other day at the dose of 15 mg/kg. As shown in Figure 7A,B, after 12 days, R-C12-4 and R-C12 have a significant inhibition effect on the BALB/c mice tumor volume compared to the control group (p < 0.01 and p < 0.05, respectively). For the metastasis model, R-C12 or R-C12-4 was applied by the tail intravenous injection every 2 days at the dose of 10 mg/kg. As shown in Figure 7D, significantly fewer metastatic nodules from the lungs of Kunming (KM) mice were observed in the R-C12-4 and R-C12 treatment groups compared to the control and this result was confirmed by the H&E staining of lung sections. Visible tumor nodules were counted on the surface of the lung demonstrating a significant difference between the control and R-C12 and R-C12-4 treatment groups (p < 0.05). It is noteworthy that both R-C12 and R-C12-4 did not affect the mouse body weight either in the subcutaneous transplantation model or in the metastasis model, indicating that these peptides did not diminish their overall health."	"In this study, we would investigate the co-modification of fatty acids and monosaccharides in anticancer peptides, as we expect to optimize the selectivity and cytotoxicity of the peptide at the same time. Based on our previous study, the lipopeptide R-C12 was selected as a template to perform glucose derivative modification at different positions as we supposed that the glucose derivative modification position in R-C12 might be a crucial factor in its selectivity and activity optimization. The glucose derivative was covalently coupled to different sites in R-C12 through its -amino group of a Lys residue, which was obtained by replacing the Arg residue. R-C12 contains seven Arg residues, accordingly, seven glycolipid peptides were designed and synthesized, which were named R-C12-1, R-C12-2, R-C12-3, R-C12-4, R-C12-5, R-C12-6, and R-C12-7. Various physiochemical properties including the hydrodynamic size, &zeta;-potential, secondary structure, and hydrophobicity were determined to explain the different cytotoxicity and selectivity of these glycolipid peptides. On the other hand, the strength of the binding between glycolipid peptides and the cancer cells mediated by GLUT1 has also been explored. The most optimized glycolipid peptide R-C12-4 demonstrated significant cytotoxicity and antimetastasis in vitro and in vivo, which indicated that it may be a good lead for anticancer drug development."
REF00588	PDC_02037	Melanoma	KM mice B16-F10 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	62.50%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	9 days	200 &mu;L 15 mg/kg	.	"For the subcutaneous transplantation model, R-C12 or R-C12-4 was injected intraperitoneally every other day at the dose of 15 mg/kg. As shown in Figure 7A,B, after 12 days, R-C12-4 and R-C12 have a significant inhibition effect on the BALB/c mice tumor volume compared to the control group (p < 0.01 and p < 0.05, respectively). For the metastasis model, R-C12 or R-C12-4 was applied by the tail intravenous injection every 2 days at the dose of 10 mg/kg. As shown in Figure 7D, significantly fewer metastatic nodules from the lungs of Kunming (KM) mice were observed in the R-C12-4 and R-C12 treatment groups compared to the control and this result was confirmed by the H&E staining of lung sections. Visible tumor nodules were counted on the surface of the lung demonstrating a significant difference between the control and R-C12 and R-C12-4 treatment groups (p < 0.05). It is noteworthy that both R-C12 and R-C12-4 did not affect the mouse body weight either in the subcutaneous transplantation model or in the metastasis model, indicating that these peptides did not diminish their overall health."	"In this study, we would investigate the co-modification of fatty acids and monosaccharides in anticancer peptides, as we expect to optimize the selectivity and cytotoxicity of the peptide at the same time. Based on our previous study, the lipopeptide R-C12 was selected as a template to perform glucose derivative modification at different positions as we supposed that the glucose derivative modification position in R-C12 might be a crucial factor in its selectivity and activity optimization. The glucose derivative was covalently coupled to different sites in R-C12 through its -amino group of a Lys residue, which was obtained by replacing the Arg residue. R-C12 contains seven Arg residues, accordingly, seven glycolipid peptides were designed and synthesized, which were named R-C12-1, R-C12-2, R-C12-3, R-C12-4, R-C12-5, R-C12-6, and R-C12-7. Various physiochemical properties including the hydrodynamic size, &zeta;-potential, secondary structure, and hydrophobicity were determined to explain the different cytotoxicity and selectivity of these glycolipid peptides. On the other hand, the strength of the binding between glycolipid peptides and the cancer cells mediated by GLUT1 has also been explored. The most optimized glycolipid peptide R-C12-4 demonstrated significant cytotoxicity and antimetastasis in vitro and in vivo, which indicated that it may be a good lead for anticancer drug development."
REF00588	PDC_02037	Melanoma	KM mice B16-F10 cells xenograft model.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	73.70%	%	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	12 days	200 &mu;L 15 mg/kg	.	"For the subcutaneous transplantation model, R-C12 or R-C12-4 was injected intraperitoneally every other day at the dose of 15 mg/kg. As shown in Figure 7A,B, after 12 days, R-C12-4 and R-C12 have a significant inhibition effect on the BALB/c mice tumor volume compared to the control group (p < 0.01 and p < 0.05, respectively). For the metastasis model, R-C12 or R-C12-4 was applied by the tail intravenous injection every 2 days at the dose of 10 mg/kg. As shown in Figure 7D, significantly fewer metastatic nodules from the lungs of Kunming (KM) mice were observed in the R-C12-4 and R-C12 treatment groups compared to the control and this result was confirmed by the H&E staining of lung sections. Visible tumor nodules were counted on the surface of the lung demonstrating a significant difference between the control and R-C12 and R-C12-4 treatment groups (p < 0.05). It is noteworthy that both R-C12 and R-C12-4 did not affect the mouse body weight either in the subcutaneous transplantation model or in the metastasis model, indicating that these peptides did not diminish their overall health."	"In this study, we would investigate the co-modification of fatty acids and monosaccharides in anticancer peptides, as we expect to optimize the selectivity and cytotoxicity of the peptide at the same time. Based on our previous study, the lipopeptide R-C12 was selected as a template to perform glucose derivative modification at different positions as we supposed that the glucose derivative modification position in R-C12 might be a crucial factor in its selectivity and activity optimization. The glucose derivative was covalently coupled to different sites in R-C12 through its -amino group of a Lys residue, which was obtained by replacing the Arg residue. R-C12 contains seven Arg residues, accordingly, seven glycolipid peptides were designed and synthesized, which were named R-C12-1, R-C12-2, R-C12-3, R-C12-4, R-C12-5, R-C12-6, and R-C12-7. Various physiochemical properties including the hydrodynamic size, &zeta;-potential, secondary structure, and hydrophobicity were determined to explain the different cytotoxicity and selectivity of these glycolipid peptides. On the other hand, the strength of the binding between glycolipid peptides and the cancer cells mediated by GLUT1 has also been explored. The most optimized glycolipid peptide R-C12-4 demonstrated significant cytotoxicity and antimetastasis in vitro and in vivo, which indicated that it may be a good lead for anticancer drug development."
REF00606	PDC_00391	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	28 &plusmn; 2.3%	%	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00396	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	57 &plusmn; 0.4%	%	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00394	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	48 &plusmn; 1.1%	%	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00398	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	31 &plusmn; 2.1%	%	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00393	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	45 &plusmn; 2.0%	%	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00397	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	35 &plusmn; 2.1%	%	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00395	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	44 &plusmn; 2.4%	%	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00392	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	40 &plusmn; 3.6%	%	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00391	Ovarian serous adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	41 &plusmn; 2.0%	%	.	.	.	.	Ovarian serous adenocarcinoma	OVCAR-3 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00396	Ovarian serous adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	12.00%	%	.	.	.	.	Ovarian serous adenocarcinoma	OVCAR-3 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00393	Ovarian serous adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	11 &plusmn; 4.1%	%	.	.	.	.	Ovarian serous adenocarcinoma	OVCAR-3 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00397	Ovarian serous adenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	28 &plusmn; 3.01%	%	.	.	.	.	Ovarian serous adenocarcinoma	OVCAR-3 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00394	Fibrosarcoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	32 &plusmn; 4.1%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00398	Fibrosarcoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	66 &plusmn; 0.5%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00395	Fibrosarcoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	36 &plusmn; 3.2%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00392	Fibrosarcoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	61 &plusmn; 0.8%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00394	Ovarian serous cystadenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	53 &plusmn; 1.4%	%	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00398	Ovarian serous cystadenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	68 &plusmn; 0.9%	%	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00395	Ovarian serous cystadenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	46 &plusmn; 0.7%	%	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00392	Ovarian serous cystadenocarcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	59 &plusmn; 1.1%	%	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00391	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00396	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00394	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00398	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00393	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00397	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00395	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00392	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00391	.	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Normal	Human fibroblast cells	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00396	.	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Normal	Human fibroblast cells	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00394	.	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Normal	Human fibroblast cells	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00398	.	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Normal	Human fibroblast cells	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00393	.	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Normal	Human fibroblast cells	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00397	.	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Normal	Human fibroblast cells	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00395	.	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Normal	Human fibroblast cells	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00606	PDC_00392	.	.	Revealed Based on the Cell Line Data	High Expreesion	Cell inhibition rate	0%	%	.	.	.	.	Normal	Human fibroblast cells	.	.	48 h	100 &mu;M	MTT assay	"NGR conjugate forms of both ibuprofen and naproxen showed improved activity when they were tested against SKOV-3 cell line which is positive for APN/CD13. Interestingly, both ibuprofen and naproxen show increased activity against this cell line when a six-carbon spacer is used for their conjugation to NGR. This is probably due to the less steric hindrance for NGR interaction with its binding protein on the cell surface. Ibuprofen-spacer-NGR and naproxen-spacer-NGR showed the same pattern of increased activity against HT-1080 tumor cells which this cell line show high expression of CD13. Surprisingly, NGR conjugates of both drugs without spacer did not show improved activity compared to the nonconjugated forms against this cell line. Therefore, it could be speculated that HT-1080 cells are more sensitive to the steric hindrance for interaction between NGR and its binding protein. None of the conjugates of ibuprofen and naproxen with or without spacer showed significantly improved activity against A2780 (as a tumor cell with normal RGD-binding protein) and OVCAR3. Therefore, it could be inferred again that the RGD motif is not qualified as a targeting tool for ibuprofen and naproxen."	"The two tripeptide sequences, arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs have been identified based on phage display studies and they have been used widely in the field of targeted drug delivery. RGD is a well-known peptide sequence for targeting integrin receptors and can bind to av&beta;3 and av&beta;5 integrin receptors subunits, which are overexpressed in the angiogenesis process of cancer cells. Because av integrin is overexpressed on the surface of cancer cells, an integrin ligand can be used as a targeting system for cancer treatment. RGD peptide conjugated with cytotoxic agents (RGD-drug conjugates) is likely to exhibit a tumor-targeting and thus antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs have been developed and showed promising activities in vitro and in vivo. Conjugation of camptothecin with RGD is an example for improving the therapeutic index of an antitumoral drug.[20c] Synthesis of dimeric RGD peptide-paclitaxel conjugate is another successful example of targeted drug delivery. Other motif that has been used for tumor targeting is NGR tripeptide. This sequence can bind to CD13 that is specially overexpressed in tumor blood vessels and is involved in angiogenesis, invasion, and metastasis. Because RGD is a peptide tag which targets the process of angiogenesis and NGR also targets tumor blood vessels, we decided to synthesize the conjugated forms of two famous NSAIDs, naproxen, and ibuprofen, with these two tripeptides. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six-carbon segment (hexanoic acid) was also used as a spacer."
REF00575	PDC_02041	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	1.79 &plusmn; 0.09 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02041	Invasive ductal carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	4.54 &plusmn; 0.71 &mu;M	&mu;M	.	.	.	.	Invasive ductal carcinoma	MCF7/PTX cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02041	Chronic myeloid leukemia	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	5.38 &plusmn; 0.25 &mu;M	&mu;M	.	.	.	.	Chronic myeloid leukemia	K562 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02041	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	1.95 &plusmn; 0.20 &mu;M	&mu;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02041	Ovarian serous cystadenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	5.92 &plusmn; 0.84 &mu;M	&mu;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02041	.	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	48.55 &plusmn; 2.94 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_00405	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	2.15 &plusmn; 0.18 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_00405	Invasive ductal carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	6.11 &plusmn; 0.61 &mu;M	&mu;M	.	.	.	.	Invasive ductal carcinoma	MCF7/PTX cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_00405	Chronic myeloid leukemia	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	5.90 &plusmn; 0.92 &mu;M	&mu;M	.	.	.	.	Chronic myeloid leukemia	K562 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_00405	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	2.69 &plusmn; 0.19 &mu;M	&mu;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_00405	Ovarian serous cystadenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	7.17 &plusmn; 0.77 &mu;M	&mu;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_00405	.	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	31.60 &plusmn; 1.88 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	1.39 &plusmn; 0.12 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Invasive ductal carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	2.92 &plusmn; 0.2 &mu;M	&mu;M	.	.	.	.	Invasive ductal carcinoma	MCF7/PTX cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Chronic myeloid leukemia	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	3.85 &plusmn; 0.9 &mu;M	&mu;M	.	.	.	.	Chronic myeloid leukemia	K562 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	1.42 &plusmn; 0.08 &mu;M	&mu;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Ovarian serous cystadenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	5.49 &plusmn; 0.36 &mu;M	&mu;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	.	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	45.21 &plusmn; 1.79 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_00404	Invasive breast carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	1.98 &plusmn; 0.14 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_00404	Invasive ductal carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	5.53 &plusmn; 0.76 &mu;M	&mu;M	.	.	.	.	Invasive ductal carcinoma	MCF7/PTX cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_00404	Chronic myeloid leukemia	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	3.82 &plusmn; 0.29 &mu;M	&mu;M	.	.	.	.	Chronic myeloid leukemia	K562 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_00404	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	2.79 &plusmn; 0.17 &mu;M	&mu;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_00404	Ovarian serous cystadenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	6.61 &plusmn; 0.94 &mu;M	&mu;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_00404	.	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	37.22 &plusmn; 2.36 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	48 h	.	MTT assay	"The anticancer activities of the conjugates were evaluated using various cancer cells (MCF-7, MCF-7/PTX, K562, A2780 and SKOV3). The IC50 values are listed in Table 3, and PTX was used for comparison. All the conjugates exhibited improved cytotoxic effects on various cancer cells. According to the results, all the conjugates showed significantly stronger antiproliferative activity than former lytic peptides (P3 and P7), and FA-P3-PTX and FA-P7-PTX showed more excellent antiproliferative activity than P3-PTX and P7-PTX in FA-overexpressing cancer cells MCF-7 (1.79 &mu;M versus 2.15 &mu;M; 1.39 &mu;M versus 1.98 &mu;M), MCF-7/PTX (4.54 &mu;M versus 6.11 &mu;M; 2.92 &mu;M versus 5.53 &mu;M), A2780 (1.95 &mu;M versus 2.69 &mu;M; 1.42 &mu;M versus 2.79 &mu;M), respectively. Thus, the conjugate FA-P3-PTX and FA-P7-PTX exhibited great antiproliferative activity on folate receptors overexpressing cancer cells, and almost equal potency to both drug resistant and -sensitive cells. Meanwhile, the conjugates showed weak toxicity to the normal cell lines HUVEC. To assess the safety profile of the designed conjugates, we examined their hemolytic activity using RBCs. As depicted in Fig. 1, all the tested peptides exhibited modest hemolytic activity."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Hepatoma	Tumor-bearing mice model with H22 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	0.00%	%	.	.	.	.	Hepatoma	H22 cell	.	.	4 days	.	.	"To study the anticancer activity of FA-P7-PTX in vivo, we performed tumor-bearing mice model with H22cells by administering once every two days peritumoral injection of FA-P7-PTX (12 &mu;mol/kg), PTX (12 &mu;mol/kg, as the positive control), or 0.9% saline as the negative control for 2 weeks. Compared with control group, the tumor volumes of the FA-P7-PTX group were dramatically reduced by 69% with no significant variation in mouse body weight. Meanwhile FA-P7-PTX exhibited stronger inhibitory effects on tumor volume compared with PTX (69% versus 49%). The result confirmed that FA-P7-PTX possessed higher potency in slowing the growth of solid tumors."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Hepatoma	Tumor-bearing mice model with H22 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	16.70%	%	.	.	.	.	Hepatoma	H22 cell	.	.	6 days	.	.	"To study the anticancer activity of FA-P7-PTX in vivo, we performed tumor-bearing mice model with H22cells by administering once every two days peritumoral injection of FA-P7-PTX (12 &mu;mol/kg), PTX (12 &mu;mol/kg, as the positive control), or 0.9% saline as the negative control for 2 weeks. Compared with control group, the tumor volumes of the FA-P7-PTX group were dramatically reduced by 69% with no significant variation in mouse body weight. Meanwhile FA-P7-PTX exhibited stronger inhibitory effects on tumor volume compared with PTX (69% versus 49%). The result confirmed that FA-P7-PTX possessed higher potency in slowing the growth of solid tumors."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Hepatoma	Tumor-bearing mice model with H22 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	38.90%	%	.	.	.	.	Hepatoma	H22 cell	.	.	8 days	.	.	"To study the anticancer activity of FA-P7-PTX in vivo, we performed tumor-bearing mice model with H22cells by administering once every two days peritumoral injection of FA-P7-PTX (12 &mu;mol/kg), PTX (12 &mu;mol/kg, as the positive control), or 0.9% saline as the negative control for 2 weeks. Compared with control group, the tumor volumes of the FA-P7-PTX group were dramatically reduced by 69% with no significant variation in mouse body weight. Meanwhile FA-P7-PTX exhibited stronger inhibitory effects on tumor volume compared with PTX (69% versus 49%). The result confirmed that FA-P7-PTX possessed higher potency in slowing the growth of solid tumors."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Hepatoma	Tumor-bearing mice model with H22 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	50.00%	%	.	.	.	.	Hepatoma	H22 cell	.	.	10 days	.	.	"To study the anticancer activity of FA-P7-PTX in vivo, we performed tumor-bearing mice model with H22cells by administering once every two days peritumoral injection of FA-P7-PTX (12 &mu;mol/kg), PTX (12 &mu;mol/kg, as the positive control), or 0.9% saline as the negative control for 2 weeks. Compared with control group, the tumor volumes of the FA-P7-PTX group were dramatically reduced by 69% with no significant variation in mouse body weight. Meanwhile FA-P7-PTX exhibited stronger inhibitory effects on tumor volume compared with PTX (69% versus 49%). The result confirmed that FA-P7-PTX possessed higher potency in slowing the growth of solid tumors."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Hepatoma	Tumor-bearing mice model with H22 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	63.00%	%	.	.	.	.	Hepatoma	H22 cell	.	.	12 days	.	.	"To study the anticancer activity of FA-P7-PTX in vivo, we performed tumor-bearing mice model with H22cells by administering once every two days peritumoral injection of FA-P7-PTX (12 &mu;mol/kg), PTX (12 &mu;mol/kg, as the positive control), or 0.9% saline as the negative control for 2 weeks. Compared with control group, the tumor volumes of the FA-P7-PTX group were dramatically reduced by 69% with no significant variation in mouse body weight. Meanwhile FA-P7-PTX exhibited stronger inhibitory effects on tumor volume compared with PTX (69% versus 49%). The result confirmed that FA-P7-PTX possessed higher potency in slowing the growth of solid tumors."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Hepatoma	Tumor-bearing mice model with H22 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	66.90%	%	.	.	.	.	Hepatoma	H22 cell	.	.	14 days	.	.	"To study the anticancer activity of FA-P7-PTX in vivo, we performed tumor-bearing mice model with H22cells by administering once every two days peritumoral injection of FA-P7-PTX (12 &mu;mol/kg), PTX (12 &mu;mol/kg, as the positive control), or 0.9% saline as the negative control for 2 weeks. Compared with control group, the tumor volumes of the FA-P7-PTX group were dramatically reduced by 69% with no significant variation in mouse body weight. Meanwhile FA-P7-PTX exhibited stronger inhibitory effects on tumor volume compared with PTX (69% versus 49%). The result confirmed that FA-P7-PTX possessed higher potency in slowing the growth of solid tumors."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Hepatoma	Tumor-bearing mice model with H22 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	65.20%	%	.	.	.	.	Hepatoma	H22 cell	.	.	16 days	.	.	"To study the anticancer activity of FA-P7-PTX in vivo, we performed tumor-bearing mice model with H22cells by administering once every two days peritumoral injection of FA-P7-PTX (12 &mu;mol/kg), PTX (12 &mu;mol/kg, as the positive control), or 0.9% saline as the negative control for 2 weeks. Compared with control group, the tumor volumes of the FA-P7-PTX group were dramatically reduced by 69% with no significant variation in mouse body weight. Meanwhile FA-P7-PTX exhibited stronger inhibitory effects on tumor volume compared with PTX (69% versus 49%). The result confirmed that FA-P7-PTX possessed higher potency in slowing the growth of solid tumors."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Hepatoma	Tumor-bearing mice model with H22 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	67.30%	%	.	.	.	.	Hepatoma	H22 cell	.	.	18 days	.	.	"To study the anticancer activity of FA-P7-PTX in vivo, we performed tumor-bearing mice model with H22cells by administering once every two days peritumoral injection of FA-P7-PTX (12 &mu;mol/kg), PTX (12 &mu;mol/kg, as the positive control), or 0.9% saline as the negative control for 2 weeks. Compared with control group, the tumor volumes of the FA-P7-PTX group were dramatically reduced by 69% with no significant variation in mouse body weight. Meanwhile FA-P7-PTX exhibited stronger inhibitory effects on tumor volume compared with PTX (69% versus 49%). The result confirmed that FA-P7-PTX possessed higher potency in slowing the growth of solid tumors."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00575	PDC_02042	Hepatoma	Tumor-bearing mice model with H22 cells.	Discovered Using Cell Line-derived Xenograft Model	.	Tumor growth inhibition value (TGI)	69.10%	%	.	.	.	.	Hepatoma	H22 cell	.	.	20 days	.	.	"To study the anticancer activity of FA-P7-PTX in vivo, we performed tumor-bearing mice model with H22cells by administering once every two days peritumoral injection of FA-P7-PTX (12 &mu;mol/kg), PTX (12 &mu;mol/kg, as the positive control), or 0.9% saline as the negative control for 2 weeks. Compared with control group, the tumor volumes of the FA-P7-PTX group were dramatically reduced by 69% with no significant variation in mouse body weight. Meanwhile FA-P7-PTX exhibited stronger inhibitory effects on tumor volume compared with PTX (69% versus 49%). The result confirmed that FA-P7-PTX possessed higher potency in slowing the growth of solid tumors."	"We have previously reported that structural optimized lytic peptides I-3 and I-7 can be used as cell-disrupting peptides and molecular carriers. Meanwhile, PTX, a firstline antitumor drug, its poor aqueous solubility (no more than 0.004mg/mL) and acquired drug resistant need to be addressed urgently. In this work, we choose the 16-site cysteine-substituted I-3 and I-7 (namely P3 and P7, respectively) served as peptide backbone and we designed a novel folate targeting peptide-PTX conjugates to achieve selective tumor delivery, enhance cellular uptake, make FA-P3/P7-PTX conjugates water-soluble and overcome drug resistance. The conjugates were evaluated for the antiproliferative activity in different cancer cell lines, the inhibitory rate of tubulin polymerization, hemolytic toxicity and water solubility. Furthermore, we assessed the conjugates for their cellular uptake, Membrane permeability, pro-apoptosis, alternation of mitochondrial membrane potential, rat plasma stability and cell apoptosis pathway in PTX resistant MCF-7/PTX cells. Finally, we researched the most optimized conjugate in vivo antitumor efficacy compared with free PTX."
REF00576	PDC_00415	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	77.9 &mu;M	&mu;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	92.5 &mu;M	&mu;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	40.2 &mu;M	&mu;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	23.4 &mu;M	&mu;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	80.1 &mu;M	&mu;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	81 &mu;M	&mu;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	77.3 &mu;M	&mu;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	71.4 &mu;M	&mu;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	82.3 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	68.8 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	35.4 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	19.7 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	89.3 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	90.5 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	80.7 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	48.6 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	.	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	75.81%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	45.17%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	56.71%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	75.80%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	79.56%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	66.18%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	65.07%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	32.42%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	77.78%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	70.56%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	72.72%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	7.78%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	9.83%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	74.57%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	78.41%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	18.02%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	17.65%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	13.21%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	10.17%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	25.25%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	34.55%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.40%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	9.63%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	15.26%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	67.09%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	9.46%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	14.61%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	12.07%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	8.30%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	16.11%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.91%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.95%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	8.69%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	7.02%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	9.55%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	8.26%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	10.21%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	8.11%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.04%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	7.95%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.41%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.80%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	7.71%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.58%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.57%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	7.28%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	7.66%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.76%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.61%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.34%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.59%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.34%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.73%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.67%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.99%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.16%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.93%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.05%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.03%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.03%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.76%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.28%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.53%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.79%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.93%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.98%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.33%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.63%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.23%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.29%	%	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	68.23%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	7.43%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	75.71%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	80.73%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	80.48%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	59.59%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	59.04%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	9.08%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	75.88%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	78.71%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	100 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	11.74%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.63%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	27.04%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	78.82%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	79.57%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	10.97%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	9.43%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	7.29%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.87%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	58.88%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	50 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.72%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.34%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.38%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	24.42%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	76.67%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	9.33%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.86%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.78%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.39%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	8.59%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	25&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.41%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.93%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.43%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	7.05%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	17.93%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	9.08%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.39%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.25%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.32%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	7.05%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	12.5 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.84%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.61%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.16%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.57%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	10.24%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	8.27%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.93%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.28%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.57%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.29%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	6.25 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.14%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.82%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.40%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.67%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6.07%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	7.61%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.81%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.15%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.44%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.89%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	3.125&mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.36%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.72%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.27%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.51%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	5.20%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	6%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.17%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.80%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.86%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.19%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	1.562 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.11%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.781 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.66%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.781 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.74%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.781 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.81%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.781 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	4.20%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.781 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.95%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.781 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.77%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.781 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.45%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.781 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.77%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.781 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.70%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.781 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.83%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.391 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.36%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.391 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.36%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.391 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.04%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.391 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	3.08%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.391 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.75%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.391 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.23%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.391 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.23%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.391 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.04%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.391 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.11%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.391 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00415	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.26%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.196 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00414	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	1.58%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.196 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00413	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	1.60%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.196 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00412	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	1.65%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.196 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00411	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.58%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.196 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00410	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	2.24%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.196 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00409	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	1.80%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.196 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00408	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	1.95%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.196 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00407	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	1.51%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.196 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00576	PDC_00406	Cervical carcinoma	.	Revealed Based on the Cell Line Data	.	Cell inhibition rate	1.92%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	72 h	0.196 &mu;M	MTT assay	"CUR-dipeptide conjugates have different degrees of inhibition of cell proliferation on HepG2 and SMMC-7721 cells. Several of the CUR-dipeptide products exhibited increased antitumor activity toward HepG2 and SMMC-7721 cells compared to that of the parent molecule (CUR), while others showed decreased activity. It could be found in Fig. 3 that CUR, 5d and 5e have obvious antitumor activities. The IC50 values of CUR, 5d and 5e against HepG2 cells were 35.8&mu;M, 40.2&mu;M and 23.4&mu;M; the IC50 values of CUR, 5d and 5e against SMMC-7721 cells were 22.9&mu;M, 35.4&mu;M and 19.7&mu;M. It is also evident from Table 1 that 5e exhibited increased cellular inhibition toward HepG2 and SMMC-7721 compared to that of the CUR, 5d performed almost the resemble activity as the parent drug. Besides, when X was Ala, anti-tumor activities of 5b and 5h almost disappeared. While the benzyl substituent (5d) was replaced with 2-methyl butyl group (5e), the activity was becoming decreased. The 5c demonstrated the best solubility, however it has relatively weak activity, which showed that great anti-tumor activity requires appropriate liposolubility. The antitumor activity of 5d (X=Phe, Y=Val) was better than that of 5i (X=Val, Y=Phe), which explained thatX=Phe plays a great important role in anti-tumor activity. This observation encouraged us to prepare the CUR derivatives modifying with rational substituents to improve its solubility and inhibition on human hepatoma cell line."	"In this study, a novel series of CUR-peptide conjugates were designed and synthesized as PepT1-mediated transport drugs and their solubility, cellular uptakes and anti-tumor activities were evaluated. The efficient and easy synthetic procedure has been outlined for the synthesis of ten novel dipeptide conjugates of CUR. All of the compounds showed higher water solubility than CUR due to the conjugation of the phenolic group to dipeptide moiety via an ether linkage. These synthesized compounds were evaluated for anti-HepG2 and anti-SMMC-7721 activity by MTT assay. Compared with CUR, compound 5e exhibited slightly stronger inhibitory activities against two liver cells and compound 5d showed the similar activity. Besides, compound 5d and 5e showed obvious higher cellular uptakes than CUR in Caco-2 cell model. The cellular uptakes of 5d and 5e were dose-dependently inhibited by PepT1 typical substrate Gly-Sar and attributed to PepT1-mediated uptake. Furthermore metabolites of compound 5d and 5e were detected and found CUR in rat liver microsomes by LC-QTOF MS. Overall, these results suggested that compound 5d and 5e have improved the absorption of CUR by PepT1-mediated without affected the activity. These new dipeptide conjugates of CUR may serve as promising lead compounds for future drug development."
REF00609	PDC_00476	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	25 &plusmn; 0.81 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00475	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	26 &plusmn; 0.60 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00474	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	23 &plusmn; 0.41 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00473	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	16 &plusmn; 0.22 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00472	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	16 &plusmn; 0.74 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00471	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	24 &plusmn; 0.36 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00470	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	24 &plusmn; 0.56 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00469	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	21 &plusmn; 0.45 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00468	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	14 &plusmn; 0.18 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00467	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	16 &plusmn; 0.59 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00466	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	30 &plusmn; 0.90 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00465	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	28 &plusmn; 0.41 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00464	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	28 &plusmn; 0.22 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00463	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	16 &plusmn; 0.24 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00462	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	17 &plusmn; 0.61 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00461	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	28 &plusmn; 0.33 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00460	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	26 &plusmn; 0.12 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00459	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	27 &plusmn; 0.61 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00458	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	15 &plusmn; 0.24 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00457	<i>Klebsiella pneumoniae</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	16 &plusmn; 0.46 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00476	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	27 &plusmn; 0.33 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00475	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	27 &plusmn; 0.35 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00474	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	25 &plusmn; 0.21 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00473	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	15 &plusmn; 0.27 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00472	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	15 &plusmn; 0.34 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00471	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	26 &plusmn; 0.31 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00470	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	26 &plusmn; 0.40 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00469	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	23 &plusmn; 0.22 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00468	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	13 &plusmn; 0.21 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00467	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	14 &plusmn; 0.36 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00466	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	31 &plusmn; 0.61 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00465	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	29 &plusmn; 0.51 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00464	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	26 &plusmn; 0.31 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00463	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	15 &plusmn; 0.28 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00462	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	18 &plusmn; 0.24 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00461	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	30 &plusmn; 0.39 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00460	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	28 &plusmn; 0.42 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00459	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	23 &plusmn; 0.47 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00458	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	13 &plusmn; 0.44 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00457	<i>Escherichia coli</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	17 &plusmn; 0.22 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00476	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	30 &plusmn; 0.26 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00475	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	29 &plusmn; 0.35 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00474	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	27 &plusmn; 0.24 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00473	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	13 &plusmn; 0.17 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00472	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	17 &plusmn; 0.15 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00471	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	27 &plusmn; 0.29 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00470	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	25 &plusmn; 0.25 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00469	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	22 &plusmn; 0.38 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00468	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	13 &plusmn; 0.34 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00467	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	14 &plusmn; 0.39 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00466	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	32 &plusmn; 0.14 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00465	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	30 &plusmn; 0.34 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00464	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	28 &plusmn; 0.28 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00463	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	15 &plusmn; 0.14 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00462	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	17 &plusmn; 0.32 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00461	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	30 &plusmn; 0.33 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00460	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	28 &plusmn; 0.36 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00459	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	23 &plusmn; 0.37 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00458	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	14 &plusmn; 0.14 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00457	<i>Aspergillus niger</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	15 &plusmn; 0.24 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00476	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	31 &plusmn; 0.36 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00475	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	30 &plusmn; 0.14 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00474	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	26 &plusmn; 0.27 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00473	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	15 &plusmn; 0.14 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00472	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	16 &plusmn; 0.16 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00471	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	27 &plusmn; 0.37 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00470	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	27 &plusmn; 0.36 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00469	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	25 &plusmn; 0.42 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00468	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	14 &plusmn; 0.48 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00467	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	13 &plusmn; 0.28 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00466	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	32 &plusmn; 0.29 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00465	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	31 &plusmn; 0.57 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00464	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	30 &plusmn; 0.54 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00463	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	16 &plusmn; 0.48 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00462	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	19 &plusmn; 0.49 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00461	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	29 &plusmn; 0.30 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00460	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	29 &plusmn; 0.29 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00459	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	26 &plusmn; 0.36 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00458	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	16 &plusmn; 0.45 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00609	PDC_00457	<i>Fusarium moniliforme</i> infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	16 &plusmn; 0.49 mm	mm	.	.	.	.	Fusarium moniliforme infection	Fusarium moniliforme	.	.	24 h	30 &mu;g/mL	.	"The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp."	"We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities."
REF00573	PDC_00498	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	400 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	160 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	250 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	250 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	120 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	250 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	80 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	20 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	40 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	60 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	60 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	40 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	40 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	20 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	40 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	100 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	24.1 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	27.3 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	25.5 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	47.3 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	21.2 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	25.6 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	27.4 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	31 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	24.8 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	28.2 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	58.4 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	23.2 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	7.3 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	10.3 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	62.3 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	57.9 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	21.8 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	15.5 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	15 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	10.6 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	6.8 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	9.8 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	131.5 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	72 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	83 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	81.5 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	82.4 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	141.5 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	63.4 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	76.7 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	94.5 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	92.9 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	74.3 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	42.2 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	174.9 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	34.8 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	21.8 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	31 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	186.5 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	173.1 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	65.3 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	46.4 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	45 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	31.6 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	20.3 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	29.4 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	393.5 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	215.4 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	100 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	100 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	100 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	100 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	100 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	100 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	100 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	100 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	36.4 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	25.9 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	36.4 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	25.8 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	37.6 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	26.4 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	33.9 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	24.6 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	108.9 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	77.4 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	108.8 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	77.3 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	112.4 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	79.1 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	101.3 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	73.5 &mu;M	&mu;M	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	.	.	"The in vitro antimycobacterial activity of the salicylanilides is preserved in the conjugates against M. tuberculosis H37Rv although their MIC values (20.3-186.5 &mu;M) are higher than the MIC of the free salicylanilides (7.5-25.9 &mu;M). There is no difference in the activity between the different salicylanilide containing OT20 or OT20(4-pal) conjugates. In terms of the peptide length, SAL2-Aoa-OT20 showed better activity than the shorter SAL2-Aoa-OT10 and the shortest SAL2-Aoa-T5 showed the best efficacy with very low MIC value (21.8 &mu;M) among these conjugates. The incorporation of the enzyme labile GFLG spacer has no significant benefit in the antimycobacterial activity of the conjugates, the MIC values of the one tuftsin unit containing conjugates with or without spacer is mostly the same. In the case of tetratuftsin derivative containing conjugate the presence of the GFLG spacer reduce its activity (SAL2-Aoa-OT20 with MIC of 81.5 &mu;M vs. SAL2-Aoa-GFLG-OT20 with MIC of 141.5 &mu;M). Among all the conjugates the short tuftsin derivative containing conjugates (namely SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH and SAL2-Aoa-TKPPR-OH) and their analogues with GFLG spacer showed outstanding in vitro antimycobacterial activity against M. tuberculosis H37Rv. The SAL2-Aoa-T5 with amide on the C-terminal was three-times more effective than its analogue SAL2-Aoa-T5-OH with C-terminal carboxyl group. The most effective conjugates are the SAL2-Aoa-TKPPR-OH (MIC value of 20.3 &mu;M) and SAL2-Aoa-T5 (MIC value of 21.8 &mu;M). Their MIC value is only three-times higher than the MIC value of the free salicylanilide SAL2. Both conjugates that contain two molecules of SAL2, i.e., SAL2-Aoa-OT20(4-SAL2-Aoa) and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) were also very effective against M. tuberculosis H37Rv with MIC values of 42.2 and 34.8 &mu;M respectively. From the perspective of the length of the fatty acid, butyric acid and decanoic acid in SAL2-Aoa-OT20(4-but) (MIC of 63.4 &mu;M) and SAL2-Aoa-OT20(4-dec) (MIC of 76.7 &mu;M) slightly improved the activity of SAL2-Aoa-OT20 (MIC of 81.5 &mu;M), their analogue without fatty acid. In the case of the palmitoylated conjugates, a slight influence of the position of palmitic acid side chain can be observed in the activity. SAL2-Aoa-OT20(4-pal) has higher MIC value (92.9 &mu;M) than SAL2-Aoa-OT20, on the contrary SAL2-Aoa-OT20(14-pal) has slightly lower MIC value (74.3 &mu;M) than SAL2-Aoa-OT20 without fatty acid. The presence of the fatty acids has a higher influence on the activity of the shorter conjugates. In the case of SAL2-Aoa-T5(4-dec) (MIC of 186.5 &mu;M) and SAL2-Aoa-T5(4-pal) (MIC of 173.1 &mu;M) the presence of these fatty acids highly reduced their activity compared to their analogue SAL2-Aoa-T5 without fatty acid (MIC of 21.8 &mu;M). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH have a low activity with high MIC values (393.5 and 215.4 &mu;M respectively). In the aspect of the MIC values calculated to the drug contents of the conjugates, most of the OT20 conjugates were effective at 25 &mu;g/mL drug content concentration, which is only 10-times higher than the MIC of the free SAL1 and SAL2 molecules (2.5 &mu;g/mL). However, among the short tuftsin derivative containing conjugates we can find compounds that have even lower MIC values calculated to drug content, between 6.8 and 10.6 &mu;g/mL (SAL2-Aoa-T5, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-TKPPR-OH and SAL2-Aoa-GFLG-TKPPR-OH). The short tuftsin derivative containing conjugates that showed outstanding activity against M. tuberculosis H37Rv sensitive strain were selected to be measured on M. tuberculosis A8 MDR strain. These conjugates can inhibit the resistant bacteria only at the highest concentration tested, at 100 &mu;g/mL (73.5-112.4 &mu;M). These MIC values are 2-5-times higher than their MIC values against the sensitive strain. In the aspect of the drug content, their average MIC value calculated to the drug content is 31 &mu;g/mL, which is 6-times higher than the MIC value of the free drug SAL2 (5 &mu;g/mL)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	100 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	100 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	100 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	80 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	160 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	200 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	12 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	13.6 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	12.7 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	23.6 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	26.5 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	25.6 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	21.9 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	24.8 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	24.8 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	47 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	18.7 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	58.1 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	58.3 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	51.7 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	62.3 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	57.9 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	72.7 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	51.7 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	75.1 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	52.9 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	67.7 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	49.1 &mu;g/mL	&mu;g/mL	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	41.5 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	40.8 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	41.2 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	70.7 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	79.3 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	76.7 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	75.6 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	74.3 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	74.3 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	70.4 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	56 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	86.9 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	174.3 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	154.8 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	186.5 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	173.1 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	217.7 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	154.6 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	224.8 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	158.2 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	202.7 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	146.9 &mu;M	&mu;M	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Mycobacterium abscessus infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	.	.	"Most of the conjugates were active also against M. abscessus. They possessed MIC values between 40.8 and 224.8 &mu;M. The salicylanilide-OT20 conjugates were the most effective against this strain. The SAL1-Aoa-OT20 (MIC = 41.5 &mu;M) and SAL2-Aoa-OT20 (MIC = 40.8 &mu;M) has similar activity as the free SAL1 (MIC = 34.5 &mu;M) and SAL2 (MIC = 59.8 &mu;M), and interestingly SAL3-Aoa-OT20 (MIC = 41.2 &mu;M) is three-times more effective than the free salicylanilide SAL3 with MIC of 129.4 &mu;M. The other tetratuftsin derivative conjugates with spacer, fatty acid side chain or second salicylanilide (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-OT20(4-but), SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal), SAL2-Aoa-OT20(14-pal) and SAL2-Aoa-OT20(4-SAL2-Aoa)) acted similarly with MICs between 70.4 and 79.3 &mu;M. Having two molecules of salicylanilide in the conjugate showed no significant advantage against M. abscessus. The MIC of SAL2-Aoa-OT20(4-SAL2-Aoa) (70.4 &mu;M) is slightly lower than the MIC of TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) (86.9 &mu;M). The dituftsin derivative containing conjugate SAL2-Aoa-OT10 had fairly good activity (MIC of 56.0 &mu;M). The shortest peptide containing conjugates were the least effective with MICs ranged from 146.9 to 224.8 &mu;M. The incorporation of GFLG spacer made the conjugates slightly more active. The presence of fatty acid side chain in the T5 containing conjugates had no significant influence on the activity against M. abscessus. According to the MIC values calculated to the drug content, the SAL1-3-Aoa-OT20 conjugates (MICdrug content is around 13 &mu;g/mL) were as effective or even more effective than the free SAL1-3 molecules (MIC within the range of 10-40 &mu;g/mL). The other OT20 derivatives with a spacer or fatty acid side chain have MIC values calculated to the drug content around 25 &mu;g/mL and the average value of the short tuftsin derivative containing conjugates is 60 &mu;g/mL."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	86.6 &plusmn; 2.8 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	24.9 &plusmn; 6.2 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	16.8 &plusmn; 3.1 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	16.5 &plusmn; 0.8 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	20.9 &plusmn; 4.0 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	39.1 &plusmn; 1.6 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	101.4 &plusmn; 5.6 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	72.6 &plusmn; 6.7 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	53.8 &plusmn; 1.1 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Acute monocytic leukemia	MONO-MAC-6 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	2.4	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	2.5	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	2.4	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.6	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	3.2	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.3	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.2	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.2	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.3	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.9	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	1.1	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	2.9	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	9.2	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	6.5	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.4	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.3	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	3.1	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	4.3	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	4.4	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	6.3	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	9.9	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	6.8	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.5	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.9	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	81.9 &plusmn; 4.2 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	112.4 &plusmn; 20.0 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	81.6 &plusmn; 2.4 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	113.3 &plusmn; 15.3 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	42.9 &plusmn; 8.9 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	37.6 &plusmn; 10.3 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	40.4 &plusmn; 17.7 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	79.7 &plusmn; 16.7 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	95.2 &plusmn; 4.2 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	162.6 &plusmn; 17.3 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	55.8 &plusmn; 3.0 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	23.2 &plusmn; 3.7 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	191.3 &plusmn; 12.4 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	58.0 &plusmn; 0.1 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	112.6 &plusmn; 26.9 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	155.6 &plusmn; 14.8 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Hepatoblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 mM	mM	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	48 h	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	2.4	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	1	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	2.4	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.8	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	1.3	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	1.5	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.5	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.4	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.5	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	1.9	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	1.1	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	2.7	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	9.2	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	5.3	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.3	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.1	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	2.9	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	1.3	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	4.4	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	3.6	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	9.9	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	5.3	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.5	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Selectivity index	0.9	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis H37Rv	.	.	.	.	MTT assay	"Most of the acetylated control peptides have no cytostatic activity on MonoMac6 and HepG2 cells at the highest concentration measured (200 &mu;M). Interestingly, among the control peptides with fatty acid modification only the derivatives that contain palmitoyl group have cytostatic effect on both cell types. Ac-OT20(4-pal) showed the lowest IC50 value on MonoMac6 (26.6 &mu;M). Its isomer with palmitic acid on the 14Lys (Ac-OT20(14-pal)) has higher IC50 value (62.8 &mu;M) on MonoMac6. Inversely, the Ac-OT20(14-pal) has lower IC50 value (35.2 &mu;M) than Ac-OT20(4-pal) (77.0 &mu;M) on HepG2 cells. In the case of the shorter Ac-T5(4-pal) it has similar effect like Ac-OT20(14-pal) on both cells. The cytostatic effect of palmitic acid itself and the physical mixture of palmitic acid and Ac-OT20 control peptide was also studied on MonoMac6 cells, and the IC50 values are very similar (178.1 and 175.8 &mu;M respectively). The covalent bond between the palmitic acid and the peptide in the most cytostatic derivative Ac-OT20(4-pal) gives almost 7-times lower IC50 value than in the case of the palmitic acid alone. In the case of the salicylanilide-tuftsin conjugates the results are diverse (Table 3). The conjugates with one tuftsin units (SAL2-Aoa-T5, SAL2-Aoa-T5-OH, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) and their analogues elongated with GFLG spacer have no cytostatic activity on MonoMac6 cells at the highest measured concentration (200 &mu;M). Conjugates with two and four tuftsin units without a side chain modification (SAL2-Aoa-OT10, SAL1-Aoa-OT20, SAL2-Aoa-OT20, SAL3-Aoa-OT20) also does not show cytostatic effects on this cell. The OT20 conjugate elongated with the GFLG spacer (SAL2-Aoa-GFLG-OT20) has a slight cytostatic activity on MonoMac6 (IC50 of 86.6 &mu;M). The presence of two salicylanilide molecules in the conjugate results in the appearance of cytostatic activity, namely SAL2-Aoa-OT20(4-SAL2-Aoa) with 39.1 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with IC50 of 101.4 &mu;M for MonoMac6 cells. The conjugates in which there are fatty acid side chain modification showed a significant cytostatic activity on MonoMac6 cells. The conjugate that have the shortest fatty acid side chain modification (with butanoyl side chain SAL2-Aoa-OT20(4-but)) has no cytostatic activity as an exception. All the palmitoyl side chain containing OT20 conjugates have very low and similar IC50 values (16.5-20.9 &mu;M) and the T5 analogue (SAL2-Aoa-T5(4-pal)) has higher IC50 value (53.8 &mu;M). The two conjugates that have decanoyl side chain modification also have cytostatic activity. The SAL2-Aoa-OT20(4-dec) has IC50 value of 24.9 &mu;M that is comparable with its analogue that have palmitoyl side chain modification (SAL2-Aoa-OT20(4-pal), 16.8 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has higher IC50 value (72.6 &mu;M) than SAL2-Aoa-T5(4-pal) (53.8 &mu;M). The finding that the decanoyl containing conjugates have cytostatic activity is in contrast that we experienced in the case of the control peptides (Ac-OT20(4-dec), Ac-T5(4-dec)) that did not show cytostatic activity nor the decanoic acid itself on MonoMac6 cells. On HepG2 cells one OT20 conjugate (SAL2-Aoa-OT20) has a slight cytostatic activity (81.9 &mu;M), the others (SAL1-Aoa-OT20, SAL3-Aoa-OT20) and the OT10 derivative SAL2-Aoa-OT10 do not exhibited this action at the highest concentration measured. The conjugates with one tuftsin unit (SAL2-Aoa-T5, SAL2-Aoa-TKPR-OH, SAL2-Aoa-TKPPR-OH) do not have cytostatic activity on HepG2 below 200 &mu;M except SAL2-Aoa-T5-OH which has a slight cytostatic effect with IC50 value of 191.3 &mu;M. Interestingly, the presence of the GFLG spacer (SAL2-Aoa-GFLG-OT20, SAL2-Aoa-GFLG-T5, SAL2-Aoa-GFLG-T5-OH, SAL2-Aoa-GFLG-TKPR-OH, SAL2-Aoa-GFLG-TKPPR-OH) makes the conjugates slightly cytostatic on HepG2 cells (IC50 values between 58.0 and 162.6 &mu;M). The conjugates containing two salicylanilide molecules have similar IC50 values to SAL2-Aoa-OT20, SAL2-Aoa-OT20(4-SAL2-Aoa) with 79.7 &mu;M and TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) with 95.2 &mu;M IC50 value. The conjugates with palmitic acid side chain modification showed a significant cytostatic activity on HepG2 cells too. The palmitoyl side chain containing OT20 conjugates have low and similar IC50 values (37.6-42.9 &mu;M). Interestingly, the T5 analogue (SAL2-Aoa-T5(4-pal)) has the lowest IC50 value among all the conjugates (23.2 &mu;M). SAL2-Aoa-OT20 and its analogue with butanoyl side chain (SAL2-Aoa-OT20(4-but)) has the same effect (81.9 and 81.6 &mu;M respectively). On the contrary that we can observe in the case of cytostatic activity on MonoMac6 cells, on HepG2 cells the cytostatic activity of the OT20 conjugate that has decanoyl side chain modification (SAL2-Aoa-OT20(4-dec)) is decreased (113.3 &mu;M). The T5 analogue SAL2-Aoa-T5(4-dec) has a higher cytostatic activity but its IC50 value (55.8 &mu;M) is still lower than the IC50 value of SAL2-Aoa-T5(4-pal) (23.2 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	4	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	40	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	0	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	15	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	20	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	25	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	0	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	4	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	15	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	60	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	0	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	60	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	10	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	1	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	11	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00492	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00491	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	10	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	0	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium tuberculosis infection	Mycobacterium tuberculosis	.	.	4 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00498	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	60	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00497	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	1	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00496	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	0	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00495	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	21	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00494	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	11	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00493	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	20	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00490	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	15	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00489	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	0	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00488	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	0	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00487	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	8	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00486	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	12	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00485	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	50	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00484	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	0	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00483	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	5	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00482	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	10	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00481	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	60	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00480	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	1	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00479	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	22	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00478	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	13	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_00477	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	15	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02043	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00573	PDC_02044	Tuberculosis	.	Revealed Based on the Cell Line Data	.	Colony forming unit	Not detected	.	.	.	.	.	Mycobacterium abscessus infection	Mycobacterium abscessus	.	.	1 weeks	250 &mu;M	.	"INH was also tested and did not show antitubercular activity against intracellular bacteria even at 365 &mu;M concentration. The free salicylanilide derivatives did not exhibit intracellular antitubercular activity at none of the used concentrations. In contrast, most of the conjugates significantly reduced the colony forming units (CFU) of intracellular M. tuberculosis bacteria compared to untreated control in a concentration dependent manner. Among the OT20 conjugates SAL1-Aoa-OT20 was more effective than SAL2-Aoa-OT20 and SAL3-Aoa-OT20 at both concentrations. However, in the case of SAL1-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(4-pal) the activity was very similar. In terms of the length of the tuftsin derivatives at 125 &mu;M there is no significant difference, at 250 &mu;M the smallest SAL2-Aoa-T5 was the most effective followed by the longest SAL2-Aoa-OT20. SAL2-Aoa-OT10 resulted in approximately 5-times higher CFU than SAL2-Aoa-T5. The presence of the GFLG spacer in the case of most peptide has no influence on the activity, only in the case of SAL2-Aoa-TKPR-OH, the presence of the spacer reduced its activity 25-times (SAL2-Aoa-GFLG-TKPR-OH). At 250 &mu;M the SAL2-Aoa-T5 with amide on the C-terminal was 10-times more effective than its analogue SAL2-Aoa-T5-OH with carboxyl group on the C-terminal of the peptide. The same tendency can be observed in the case of the derivatives of these peptides with GFLG spacer (SAL2-Aoa-GFLG-T5 vs. SAL2-Aoa-GFLG-T5-OH). The OT20 derivative which contains two molecules of salicylanilides, SAL2-Aoa-OT20(4-SAL2-Aoa) showed a weaker activity than its analogue with only one drug molecule SAL2-Aoa-OT20. The conjugate TKPR-OT10(8-SAL2-Aoa; 13-SAL2-Aoa) that contains also two salicylanilides has better activity than SAL2-Aoa-OT20(4-SAL2-Aoa). It was also more effective than SAL2-Aoa-OT20 and SAL2-Aoa-OT10 at 250 &mu;M concentration, but less effective than SAL2-Aoa-TKPR. SAL2-Aoa-OT20(4-but) has slightly better activity than SAL2-Aoa-OT20 conjugate without fatty acid side chain. The decanoic or palmitic acid side chain containing OT20 derivative (SAL2-Aoa-OT20(4-dec), SAL1-Aoa-OT20(4-pal), SAL2-Aoa-OT20(4-pal) and SAL2-Aoa-OT20(14-pal)) were outstandingly effective both at 125 and 250 &mu;M concentration. At 250 &mu;M SAL2-Aoa-OT20(4-pal) resulted in 5-times lower CFU value than its analogue where the palmitic acid is on the 14th amino acid residue (SAL2-Aoa-OT20(14-pal)). In the case of the T5 derivatives both fatty acid containing conjugates SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal) showed a better activity than SAL2-Aoa-T5 without fatty acid side chain. Interestingly at 125 &mu;M the decanoic acid containing derivative proved to be better than the palmitic acid containing one, but this result is reversed at 250 &mu;M. The OT20 derivatives containing the fatty acids (SAL2-Aoa-OT20(4-dec) and SAL2-Aoa-OT20(4-pal)) showed a more improved effect in comparison with T5 derivatives SAL2-Aoa-T5(4-dec) and SAL2-Aoa-T5(4-pal). The smallest metabolites produced during lysosomal degradation, SAL2-Aoa-Thr-OH and SAL2-Aoa-Gly-OH, also showed an activity against the intracellular bacteria without dependence of concentration. They can reduce the CFU values similarly as e.g., conjugate SAL2-Aoa-OT10, SAL2-Aoa-TKPPR-OH or SAL2-Aoa-GFLG-TKPPR-OH (at 250 &mu;M)."	"INH-tuftsin conjugates GTKPK(INH-CH2-CO)G and [TKPK(INH-CH2-CO)G]4 were effective against M. tuberculosis and the minimal inhibitory concentration values were comparable to the free INH moiety. Enhanced cellular uptake and significant inhibition of intracellular M. tuberculosis was performed by conjugation of new in silico identified drug candidate to [TKPKG]4 tuftsin derivative (TB5-OT20). Tuftsin based conjugates of pyridopyrimidine derivatives with in vitro antitubercular activity presented increased membrane affinity on lipid model systems. Palmitoylated tuftsin conjugate of INH (pal-T5(INH)2, where T5 is TKPKG) and new in silico identified drug candidate (pal-T5(TB820)2) was found to be effective against susceptible and multiresistant M. tuberculosis strains with a relatively high in vitro selectivity. Free INH did not exhibit intracellular antitubercular activity, in contrast, its pal-T5(INH)2 conjugate significantly inhibited the intracellular M. tuberculosis. The palmitoylated conjugates were encapsulated into PLGA (poly(lactide-co-glycolide)) nanoparticles with high encapsulation efficacy and the encapsulated compound showed high in vivo efficacy and low toxicity. In this study various tuftsin derivatives such as tetramer [TKPKG]4 (OT20), heterotrimer TKPR-[TKPKG]2 (TKPR-OT10), dimer [TKPKG]2 (OT10) and monomer tuftsin derivatives TKPKG (T5), TKPR, TKPPR (tuftsin antagonist) were used as carrier peptides. Tuftsin derivatives with modified Lys residues (e.g., introduction of palmitic acid, decanoic acid or butyric acid) were also studied. Modification with fatty acid chains can enhance the lipophilicity, membrane affinity and encapsulation efficacy. Modified conjugable salicylanilides were attached to the tuftsin derivatives via oxime bond directly or by the insertion of a spacer between the drug molecule and the carrier. The oxime bond is chemically stable between pH 3 and 8, the incorporation of an enzymatic cleavable spacer between the drug and the carrier moiety might be necessary for the efficient drug release and activity. As spacer, the enzyme labile GFLG tetrapeptide was applied, which could be cleaved by the lysosomal cysteine protease, cathepsin B. Here we report the synthesis, chemical characterization, in vitro extracellular and intracellular antimycobacterial activity, cytotoxic and cytostatic activity, cellular uptake, membrane integrity studies and lysosomal degradation of salicylanilide-tuftsin conjugates."
REF00574	PDC_00503	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	 80 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00502	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	52 &plusmn; 1 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00500	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	6.0 &plusmn; 3.3 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00501	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	7 &plusmn; 2 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00499	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	20 &plusmn; 2 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00503	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	 80 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00502	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	57 &plusmn; 0.8 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00500	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	7.0 &plusmn; 1.4 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00501	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	6.0 &plusmn; 0.1 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00499	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	61 &plusmn; 2 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00503	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00502	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Minimum inhibitory concentration (MIC)	74 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00500	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Minimum inhibitory concentration (MIC)	18 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00501	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Minimum inhibitory concentration (MIC)	13 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00499	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Minimum inhibitory concentration (MIC)	37 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00503	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Minimum inhibitory concentration (MIC)	Not detected	.	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00502	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Minimum inhibitory concentration (MIC)	68 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00500	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Minimum inhibitory concentration (MIC)	18 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00501	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Minimum inhibitory concentration (MIC)	13 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00499	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Minimum inhibitory concentration (MIC)	147 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	24 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00503	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	 800 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus infection strain	.	.	2 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00502	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	800 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus infection strain	.	.	2 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00500	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	25 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus infection strain	.	.	2 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00501	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	25 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus infection strain	.	.	2 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00499	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	200 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus infection strain	.	.	2 h	.	.	"As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00500	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	 80 &mu;M	&mu;M	.	.	.	.	Normal	Human fibroblast strain 1	.	.	24 h	.	CCK-8 assay	"To assess whether our most potent NA-peptide conjugates would possess a therapeutic window compatible with low levels of human toxicity, two types of human fibroblasts were treated with NA, compound 4, and the unconjugated peptide. The IC50 values were >10-fold higher for the fibroblasts versus the S. aureus strains tested. This trend indicates that the drug conjugates may possess a suitable therapeutic window for successful application as antibacterial agents."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00574	PDC_00500	<i>Staphylococcus aureus</i> infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	 80 &mu;M	&mu;M	.	.	.	.	Normal	Human fibroblast strain 2	.	.	24 h	.	CCK-8 assay	"To assess whether our most potent NA-peptide conjugates would possess a therapeutic window compatible with low levels of human toxicity, two types of human fibroblasts were treated with NA, compound 4, and the unconjugated peptide. The IC50 values were >10-fold higher for the fibroblasts versus the S. aureus strains tested. This trend indicates that the drug conjugates may possess a suitable therapeutic window for successful application as antibacterial agents."	"Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug."
REF00572	PDC_00532	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	6.3 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00535	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	3.1 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00534	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	1.6 &mu;M	&mu;M	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00533	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	3.1 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00536	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	12.5 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00532	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum bactericidal concentration (MBC)	6.3 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00535	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum bactericidal concentration (MBC)	3.1 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00534	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum bactericidal concentration (MBC)	3.1 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00533	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum bactericidal concentration (MBC)	4.2 &plusmn; 1.8 &mu;M	&mu;M	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00536	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum bactericidal concentration (MBC)	12.5 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00532	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	25.0 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00535	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	12.5 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00534	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	12.5 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00533	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	12.5 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00536	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	25.0 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00532	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum bactericidal concentration (MBC)	33.3 &plusmn; 14.4 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00535	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum bactericidal concentration (MBC)	20.8 &plusmn; 7.2 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00534	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum bactericidal concentration (MBC)	25.0 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00533	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum bactericidal concentration (MBC)	14.6 &plusmn; 9.5 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00536	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum bactericidal concentration (MBC)	25.0 &plusmn; 0.0 &mu;M	&mu;M	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	18 h	.	.	"We first investigated the antimicrobial potency of these new MAAPCs by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Escherichia coli (E. coli MG1655) and Staphylococcus aureus (SA113) pathogens with a turbidity-based microdilution broth assay. Overall, all the MAAPCs display good antimicrobial activity and tend to be more selective to E. coli (MIC range 3.1-12.5 &mu;M) over S. aureus (MIC range 12.5-25 &mu;M), which follows the general observation that tobramycin is particularly active against Gram-negative organisms. Their MBC values are either equal to or slightly higher than their respective MIC values suggesting that the compounds not only are inhibiting bacterial growth but are also bactericidal. In contrast, the unconjugated peptides (P1-P4) exhibited no or little antimicrobial activity against E. coli and S. aureus. However, the MAAPCs did not show better activity than tobramycin, which is expected because our conjugates are not designed to target lab strains but instead to have high efficacy against clinically relevant pathogens such as persisters, resistant bacteria, and anaerobes that are impermeable to existing antibiotics. It should be noted that a mixture of the peptide itself with tobramycin does not enhance the antimicrobial activity compared to tobramycin alone, indicating there is no synergistic effect between the two entities when simply mixed. Whereas MAAPC05 showed similar activity against S. aureus in comparison to MAAPC01 (indicating that the terminus of conjugation did not greatly impact activity), it displayed a 2-fold increase of the MIC against E. coli. In contrast, MAAPC02, MAAPC03, and MAAPC04 displayed improved activity compared to MAAPC01. These results indicate the importance of the peptide transporter sequence as well as the conjugation site for tobramycin. Interestingly, MAAPC02 and MAAPC03 have nearly identical amino-acid composition as MAAPC01 (the only difference is a single glycine), but the amino acids are in a different sequence. In the MAAPC02 analog, the hydrophobic amino acids are clustered along one side of the -helical wheel of the peptide, which confers higher amphiphilic character and greater helical propensity. In the MAAPC03 analog, the peptide has the reversed sequence of MAAPC01. There are examples in the literature that the reversed analogs of antimicrobial peptides possess equal or enhanced antimicrobial activities. The amphiphilicity and peptide sequence orientation might play a role on the membrane-peptide interaction. However, further experiments are required to elucidate the reasons for this improved antibacterial activity."	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00532	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	516.5 &mu;M	&mu;M	.	.	.	.	Normal	Human red blood cells	.	.	1 h	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00535	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	1000 &mu;M	&mu;M	.	.	.	.	Normal	Human red blood cells	.	.	1 h	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00534	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	1000 &mu;M	&mu;M	.	.	.	.	Normal	Human red blood cells	.	.	1 h	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00533	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	2000 &mu;M	&mu;M	.	.	.	.	Normal	Human red blood cells	.	.	1 h	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00536	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	676.7 &mu;M	&mu;M	.	.	.	.	Normal	Human red blood cells	.	.	1 h	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00532	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	82.64	.	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	.	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00535	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	320	.	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	.	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00534	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	320	.	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	.	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00533	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	640	.	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	.	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00536	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	54.14	.	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	.	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00532	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	20.66	.	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	.	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00535	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	80	.	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	.	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00534	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	80	.	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	.	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00533	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	160	.	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	.	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00572	PDC_00536	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	27.07	.	.	.	.	.	Staphylococcus aureus infection	Staphylococcus aureus	.	.	.	.	.	"One of the limitations to the clinical use of AMPs as antimicrobial agents is their hemolytic activity which is associated with increased toxicity. Thus, as a first assessment of the MAAPC toxicity, we investigated whether the conjugates may cause lysis of human red blood cells (hRBCs). Notably, all MAAPCs exhibited negligible hemolytic activity against hRBCs (HC50 > 500 &mu;M), which is the first indicator of the MAAPC safety toward eukaryotic cells. Bacterial and animal cell membranes significantly differ in composition. Indeed, microbial cell surfaces contain more anionic lipids (overall negatively charged) whereas mammalian cell membranes have more lipids with neutral zwitterionic head groups (overall neutrally charged). The MAAPCs were designed to selectively discriminate between bacterial and mammalian cells. The selectivity indexes (SIs), defined as HC50/MIC, for E. coli and S. aureus demonstrated great selectivity of all MAAPCs to bacteria over hRBCs, which implies that the MAAPCs are effective against bacteria without causing harm to human cells. MAAPC04 displayed the highest bacterial selectivity (SI > 640 and SI > 160 against E. coli and S. aureus, respectively) likely due to its reduced hydrophobic content. "	"We have synthesized a series of MAAPCs incorporating tobramycin with variations in the composition, sequence, and conjugation site of the peptide transporter. The MAAPCs exhibit good selectivity for bacterial cell membranes over mammalian cell membranes and do not induce any significant hemolysis of human red blood cells. MAAPCs exhibit better antibacterial activity against actively growing Gram-negative E. coli (MIC < 15 &mu;M) than actively growing Gram-positive S. aureus (MIC < 25 &mu;M). MAAPC01 exhibits the highest permeabilization of the outer membrane, with all other MAAPCs showing less permeation activity; tobramycin exhibits no outer membrane activity. MAAPC01 and MAAPC05 exhibit the highest inner membrane permeability, comparable to the control melittin. MAAPC02 and 03 exhibit less membrane activity, and MAAPC04 and tobramycin show negligible inner membrane activity. Higher levels of membrane activity correlate well with antimicrobial activity against persisters, where MAAPC01 and MAAPC05 show much better activity than tobramycin alone or MAAPC04."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	13 &plusmn; 0.26 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	6 &plusmn; 0.21 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	5 &plusmn; 0.26 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	15 &plusmn; 0.47 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	16 &plusmn; 0.25 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	18 &plusmn; 0.28 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	20 &plusmn; 0.30 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	24 &plusmn; 0.15 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	22 &plusmn; 0.20 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	20 &plusmn; 0.30 mm	mm	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	11 &plusmn; 0.20 mm	mm	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	5 &plusmn; 0.10 mm	mm	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	5 &plusmn; 0.05 mm	mm	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	14 &plusmn; 0.30 mm	mm	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	16 &plusmn; 0.05 mm	mm	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	17 &plusmn; 0.25 mm	mm	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	18 &plusmn; 0.37 mm	mm	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	20 &plusmn; 0.36 mm	mm	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	21 &plusmn; 0.36 mm	mm	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	18 &plusmn; 0.32 mm	mm	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	10 &plusmn; 0.30 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	5 &plusmn; 0.10 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	3 &plusmn; 0.30 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	12 &plusmn; 0.36 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	14 &plusmn; 0.30 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	15 &plusmn; 0.10 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	17 &plusmn; 0.40 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	19 &plusmn; 0.23 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	21 &plusmn; 0.26 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	20 &plusmn; 0.40 mm	mm	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	9 &plusmn; 0.20 mm	mm	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	4 &plusmn; 0.11 mm	mm	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	4 &plusmn; 0.26 mm	mm	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	11 &plusmn; 0.47 mm	mm	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	15 &plusmn; 0.43 mm	mm	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	15 &plusmn; 0.20 mm	mm	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	17 &plusmn; 0.17 mm	mm	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	20 &plusmn; 0.30 mm	mm	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	22 &plusmn; 0.30 mm	mm	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	20 &plusmn; 0.05 mm	mm	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	15 &plusmn; 0.36 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	7 &plusmn; 0.20 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	5 &plusmn; 0.10 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	18 &plusmn; 0.40 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	22 &plusmn; 0.41 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	24 &plusmn; 0.36 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	29 &plusmn; 0.52 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	31 &plusmn; 0.40 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	38 &plusmn; 0.43 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	37 &plusmn; 0.47 mm	mm	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	11 &plusmn; 0.15 mm	mm	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	5 &plusmn; 0.05 mm	mm	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	4 &plusmn; 0.41 mm	mm	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	14 &plusmn; 0.25 mm	mm	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	16 &plusmn; 0.34 mm	mm	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	17 &plusmn; 0.25 mm	mm	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	19 &plusmn; 0.26 mm	mm	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	21 &plusmn; 0.32 mm	mm	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	29 &plusmn; 0.32 mm	mm	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	26 &plusmn; 0.26 mm	mm	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	15 &plusmn; 0.10 mm	mm	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	5 &plusmn; 0.15 mm	mm	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	5 &plusmn; 0.47 mm	mm	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	17 &plusmn; 0.45 mm	mm	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	19 &plusmn; 0.30 mm	mm	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	20 &plusmn; 0.55 mm	mm	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	22 &plusmn; 0.25 mm	mm	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	23 &plusmn; 0.41 mm	mm	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	31 &plusmn; 0.30 mm	mm	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Zone of inhibition	29 &plusmn; 0.10 mm	mm	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	24 h	50 &mu;g/ml	Agar well diffusion method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	20 &mu;g/mL	&mu;g/mL	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	39 &mu;g/mL	&mu;g/mL	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	41 &mu;g/mL	&mu;g/mL	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	17 &mu;g/mL	&mu;g/mL	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	15 &mu;g/mL	&mu;g/mL	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	14 &mu;g/mL	&mu;g/mL	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	11 &mu;g/mL	&mu;g/mL	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	8 &mu;g/mL	&mu;g/mL	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	10 &mu;g/mL	&mu;g/mL	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	12 &mu;g/mL	&mu;g/mL	.	.	.	.	Escherichia coli infection	Escherichia coli	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	16 &mu;g/mL	&mu;g/mL	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	27 &mu;g/mL	&mu;g/mL	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	29 &mu;g/mL	&mu;g/mL	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	14 &mu;g/mL	&mu;g/mL	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	12 &mu;g/mL	&mu;g/mL	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	12 &mu;g/mL	&mu;g/mL	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	10 &mu;g/mL	&mu;g/mL	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	8 &mu;g/mL	&mu;g/mL	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	9 &mu;g/mL	&mu;g/mL	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	11 &mu;g/mL	&mu;g/mL	.	.	.	.	Xanthomonas oryzae infection	Xanthomonas oryzae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	17 &mu;g/mL	&mu;g/mL	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	31 &mu;g/mL	&mu;g/mL	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	35 &mu;g/mL	&mu;g/mL	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	14 &mu;g/mL	&mu;g/mL	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	13 &mu;g/mL	&mu;g/mL	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	11 &mu;g/mL	&mu;g/mL	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	9 &mu;g/mL	&mu;g/mL	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	6 &mu;g/mL	&mu;g/mL	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	9 &mu;g/mL	&mu;g/mL	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	10 &mu;g/mL	&mu;g/mL	.	.	.	.	Klebsiella pneumoniae infection	Klebsiella pneumoniae	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	18 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	35 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	38 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	15 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	13 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	11 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	10 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	7 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	12 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	13 &mu;g/mL	&mu;g/mL	.	.	.	.	Staphylococcus infection	Staphylococcus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	18 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	32 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	34 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	16 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	14 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	12 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	8 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	6 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	3 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	4 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus niger infection	Aspergillus niger	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	21 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	42 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	48 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	17 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	16 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	15 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	9 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	8 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	3 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	3 &mu;g/mL	&mu;g/mL	.	.	.	.	Aspergillus flavus infection	Aspergillus flavus	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01017	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	21 &mu;g/mL	&mu;g/mL	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01018	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	39 &mu;g/mL	&mu;g/mL	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01019	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	43 &mu;g/mL	&mu;g/mL	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01020	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	19 &mu;g/mL	&mu;g/mL	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01021	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	18 &mu;g/mL	&mu;g/mL	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01022	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	16 &mu;g/mL	&mu;g/mL	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01023	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	11 &mu;g/mL	&mu;g/mL	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01024	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	7 &mu;g/mL	&mu;g/mL	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01025	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	4 &mu;g/mL	&mu;g/mL	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00608	PDC_01026	Bacterial infection	.	Revealed Based on the Cell Line Data	.	Minimum inhibitory concentration (MIC)	5 &mu;g/mL	&mu;g/mL	.	.	.	.	Fusarium oxysporum infection	Fusarium oxysporum	.	.	16-18 h	.	Microdilution method	"Based on this observation we were very much projected towards the conjugation of elastin based peptides with varying chain length and hydrophobicity. We focused our attention on tetrapeptide elastin sequences with varying hydrophobicity. Among the analogs tested GGAP (29), GGIP (30) and GGFP (31), the latter has exhibited more activity i.e., GGFP with Phe unit has exerted nearly two times more potent activity than the antibiotics used where as the other two tetrapeptides conjugated heterocycle have shown comparatively less activity than GGFP which could be due to less hydrophobicity of amino acids present at the second position. Thus the order of activity among tetrapeptide conjugates is GGFP > GGIP > GGAP. In the light of the above findings, our subsequent goal was to incorporate GVGVP and GFGFP pentapeptide elastin sequences for conjugation. The pentapeptide conjugates have shown more than two fold potent activity compared to reference drugs used. Among these, GFGFP conjugate (33) has shown slight enhancement in the activity over GVGVP conjugate (32) which may be due to the presence of two more hydrophobic Phe units in 33. Inspection of the results further revealed that the conjugate 26 having single Phe residue has shown enhanced activity. On the other hand, retaining of only one Phe unit and increasing the peptide chain length has caused further increase in the activity (~two times) which is evident from the conjugate GGFP (31). Similarly, the remaining two tetrapeptide conjugates GGIP and GGAP have shown increased activity compared to Phe alone (26). Also, when the length of the peptide chain increased as well as two Phe residues were introduced (greater hydrophobicity) as in GFGFP (33) has exhibited two times greater activity than the standard drugs. This trend was followed in GVGVP conjugate (32) also. Hence, it can be inferred that as the length of the peptide chain as well as the hydrophobicity increases the activity also increases. Thus, the order of activity of the heterocyclic conjugated peptides is found to be GFGFP > GVGVP > GGFP > GGIP > GGAP > Phe > Trp > Tyr."	"Elastin protein-based polymers have their origin in repeating sequences of the mammalian elastic protein, elastin. The sequences of elastin peptides chosen are tetrapeptides, pentapeptides and tricosamers (30 amino acids) and also aromatic amino acids. These have been conjugated to 1-(2,3-dichlorophenyl)piperazine to study the effect of conjugation on the activity. The conjugates so obtained were characterized by physical and analytical techniques followed by the antimicrobial evaluation. The study revealed that all the conjugates have exhibited enhanced activity than the conventional drugs. Further, the conjugates of tricosamers have shown extraordinary activity against the fungal species with MIC value of 3-5 &mu;g/ml which is five fold more potent than the antibiotic used."
REF00571	PDC_01080	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Haemozoin inhibition	50%	%	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	.	.	.	"The capacity of test compounds 8 and 9 to inhibit heme polymerization in vitro was assessed by previously reported methods, given in detail under Experimental. The assays were run in 96-well microplates, where negative controls (water, DMSO) and positive controls (1 mM CQ) were included. Test compounds were assayed at 1 mM and data are given in Table 1. Interestingly, the dipeptide spacer was required to block heme polymerization, i.e., while HECINs 9 were not active, HEDICINs 8 displayed variable inhibitory efficiencies, with four out of the twelve compounds (8b, 8e, 8j and 8l) highly active (i.e., comparable to the reference drug, CQ). Though no clear trend could be established regarding stereoelectronic properties of the aryl substituent in compounds 8, it was clear that: (i) hydrogen (i.e., absence of a substituent) or halogens in the para position were detrimental for activity, whereas (ii) nitrogenated groups at either the ortho (8j, o-NO2) or the para (8e, p-NH2; 8l, p-NO2) position of the aryl ring was beneficial, but (iii) detrimental if placed in the meta position (8k, m-NO2). Furthermore, while small alkyl groups in para (8b, p-Me) were advantageous, bulkier groups as in 8c (p-iPr) led to complete loss of activity. Thus, replacement of CQ's aliphatic chain by an adequate dipeptidyl-cinnamoyl moiety as in 8b, 8e, 8j and 8l appears to preserve the parent drug's ability to inhibit hemozoin formation, suggesting that these novel compounds could be promising leads for new CQ surrogates."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01079	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Haemozoin inhibition	75%	%	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	.	.	.	"The capacity of test compounds 8 and 9 to inhibit heme polymerization in vitro was assessed by previously reported methods, given in detail under Experimental. The assays were run in 96-well microplates, where negative controls (water, DMSO) and positive controls (1 mM CQ) were included. Test compounds were assayed at 1 mM and data are given in Table 1. Interestingly, the dipeptide spacer was required to block heme polymerization, i.e., while HECINs 9 were not active, HEDICINs 8 displayed variable inhibitory efficiencies, with four out of the twelve compounds (8b, 8e, 8j and 8l) highly active (i.e., comparable to the reference drug, CQ). Though no clear trend could be established regarding stereoelectronic properties of the aryl substituent in compounds 8, it was clear that: (i) hydrogen (i.e., absence of a substituent) or halogens in the para position were detrimental for activity, whereas (ii) nitrogenated groups at either the ortho (8j, o-NO2) or the para (8e, p-NH2; 8l, p-NO2) position of the aryl ring was beneficial, but (iii) detrimental if placed in the meta position (8k, m-NO2). Furthermore, while small alkyl groups in para (8b, p-Me) were advantageous, bulkier groups as in 8c (p-iPr) led to complete loss of activity. Thus, replacement of CQ's aliphatic chain by an adequate dipeptidyl-cinnamoyl moiety as in 8b, 8e, 8j and 8l appears to preserve the parent drug's ability to inhibit hemozoin formation, suggesting that these novel compounds could be promising leads for new CQ surrogates."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01078	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Haemozoin inhibition	50%	%	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	.	.	.	"The capacity of test compounds 8 and 9 to inhibit heme polymerization in vitro was assessed by previously reported methods, given in detail under Experimental. The assays were run in 96-well microplates, where negative controls (water, DMSO) and positive controls (1 mM CQ) were included. Test compounds were assayed at 1 mM and data are given in Table 1. Interestingly, the dipeptide spacer was required to block heme polymerization, i.e., while HECINs 9 were not active, HEDICINs 8 displayed variable inhibitory efficiencies, with four out of the twelve compounds (8b, 8e, 8j and 8l) highly active (i.e., comparable to the reference drug, CQ). Though no clear trend could be established regarding stereoelectronic properties of the aryl substituent in compounds 8, it was clear that: (i) hydrogen (i.e., absence of a substituent) or halogens in the para position were detrimental for activity, whereas (ii) nitrogenated groups at either the ortho (8j, o-NO2) or the para (8e, p-NH2; 8l, p-NO2) position of the aryl ring was beneficial, but (iii) detrimental if placed in the meta position (8k, m-NO2). Furthermore, while small alkyl groups in para (8b, p-Me) were advantageous, bulkier groups as in 8c (p-iPr) led to complete loss of activity. Thus, replacement of CQ's aliphatic chain by an adequate dipeptidyl-cinnamoyl moiety as in 8b, 8e, 8j and 8l appears to preserve the parent drug's ability to inhibit hemozoin formation, suggesting that these novel compounds could be promising leads for new CQ surrogates."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01083	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Haemozoin inhibition	75%	%	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	.	.	.	"The capacity of test compounds 8 and 9 to inhibit heme polymerization in vitro was assessed by previously reported methods, given in detail under Experimental. The assays were run in 96-well microplates, where negative controls (water, DMSO) and positive controls (1 mM CQ) were included. Test compounds were assayed at 1 mM and data are given in Table 1. Interestingly, the dipeptide spacer was required to block heme polymerization, i.e., while HECINs 9 were not active, HEDICINs 8 displayed variable inhibitory efficiencies, with four out of the twelve compounds (8b, 8e, 8j and 8l) highly active (i.e., comparable to the reference drug, CQ). Though no clear trend could be established regarding stereoelectronic properties of the aryl substituent in compounds 8, it was clear that: (i) hydrogen (i.e., absence of a substituent) or halogens in the para position were detrimental for activity, whereas (ii) nitrogenated groups at either the ortho (8j, o-NO2) or the para (8e, p-NH2; 8l, p-NO2) position of the aryl ring was beneficial, but (iii) detrimental if placed in the meta position (8k, m-NO2). Furthermore, while small alkyl groups in para (8b, p-Me) were advantageous, bulkier groups as in 8c (p-iPr) led to complete loss of activity. Thus, replacement of CQ's aliphatic chain by an adequate dipeptidyl-cinnamoyl moiety as in 8b, 8e, 8j and 8l appears to preserve the parent drug's ability to inhibit hemozoin formation, suggesting that these novel compounds could be promising leads for new CQ surrogates."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01076	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Haemozoin inhibition	50%	%	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	.	.	.	"The capacity of test compounds 8 and 9 to inhibit heme polymerization in vitro was assessed by previously reported methods, given in detail under Experimental. The assays were run in 96-well microplates, where negative controls (water, DMSO) and positive controls (1 mM CQ) were included. Test compounds were assayed at 1 mM and data are given in Table 1. Interestingly, the dipeptide spacer was required to block heme polymerization, i.e., while HECINs 9 were not active, HEDICINs 8 displayed variable inhibitory efficiencies, with four out of the twelve compounds (8b, 8e, 8j and 8l) highly active (i.e., comparable to the reference drug, CQ). Though no clear trend could be established regarding stereoelectronic properties of the aryl substituent in compounds 8, it was clear that: (i) hydrogen (i.e., absence of a substituent) or halogens in the para position were detrimental for activity, whereas (ii) nitrogenated groups at either the ortho (8j, o-NO2) or the para (8e, p-NH2; 8l, p-NO2) position of the aryl ring was beneficial, but (iii) detrimental if placed in the meta position (8k, m-NO2). Furthermore, while small alkyl groups in para (8b, p-Me) were advantageous, bulkier groups as in 8c (p-iPr) led to complete loss of activity. Thus, replacement of CQ's aliphatic chain by an adequate dipeptidyl-cinnamoyl moiety as in 8b, 8e, 8j and 8l appears to preserve the parent drug's ability to inhibit hemozoin formation, suggesting that these novel compounds could be promising leads for new CQ surrogates."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01075	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Haemozoin inhibition	50%	%	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	.	.	.	"The capacity of test compounds 8 and 9 to inhibit heme polymerization in vitro was assessed by previously reported methods, given in detail under Experimental. The assays were run in 96-well microplates, where negative controls (water, DMSO) and positive controls (1 mM CQ) were included. Test compounds were assayed at 1 mM and data are given in Table 1. Interestingly, the dipeptide spacer was required to block heme polymerization, i.e., while HECINs 9 were not active, HEDICINs 8 displayed variable inhibitory efficiencies, with four out of the twelve compounds (8b, 8e, 8j and 8l) highly active (i.e., comparable to the reference drug, CQ). Though no clear trend could be established regarding stereoelectronic properties of the aryl substituent in compounds 8, it was clear that: (i) hydrogen (i.e., absence of a substituent) or halogens in the para position were detrimental for activity, whereas (ii) nitrogenated groups at either the ortho (8j, o-NO2) or the para (8e, p-NH2; 8l, p-NO2) position of the aryl ring was beneficial, but (iii) detrimental if placed in the meta position (8k, m-NO2). Furthermore, while small alkyl groups in para (8b, p-Me) were advantageous, bulkier groups as in 8c (p-iPr) led to complete loss of activity. Thus, replacement of CQ's aliphatic chain by an adequate dipeptidyl-cinnamoyl moiety as in 8b, 8e, 8j and 8l appears to preserve the parent drug's ability to inhibit hemozoin formation, suggesting that these novel compounds could be promising leads for new CQ surrogates."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01074	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Haemozoin inhibition	50%	%	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	.	.	.	"The capacity of test compounds 8 and 9 to inhibit heme polymerization in vitro was assessed by previously reported methods, given in detail under Experimental. The assays were run in 96-well microplates, where negative controls (water, DMSO) and positive controls (1 mM CQ) were included. Test compounds were assayed at 1 mM and data are given in Table 1. Interestingly, the dipeptide spacer was required to block heme polymerization, i.e., while HECINs 9 were not active, HEDICINs 8 displayed variable inhibitory efficiencies, with four out of the twelve compounds (8b, 8e, 8j and 8l) highly active (i.e., comparable to the reference drug, CQ). Though no clear trend could be established regarding stereoelectronic properties of the aryl substituent in compounds 8, it was clear that: (i) hydrogen (i.e., absence of a substituent) or halogens in the para position were detrimental for activity, whereas (ii) nitrogenated groups at either the ortho (8j, o-NO2) or the para (8e, p-NH2; 8l, p-NO2) position of the aryl ring was beneficial, but (iii) detrimental if placed in the meta position (8k, m-NO2). Furthermore, while small alkyl groups in para (8b, p-Me) were advantageous, bulkier groups as in 8c (p-iPr) led to complete loss of activity. Thus, replacement of CQ's aliphatic chain by an adequate dipeptidyl-cinnamoyl moiety as in 8b, 8e, 8j and 8l appears to preserve the parent drug's ability to inhibit hemozoin formation, suggesting that these novel compounds could be promising leads for new CQ surrogates."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01073	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Haemozoin inhibition	50%	%	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	.	.	.	"The capacity of test compounds 8 and 9 to inhibit heme polymerization in vitro was assessed by previously reported methods, given in detail under Experimental. The assays were run in 96-well microplates, where negative controls (water, DMSO) and positive controls (1 mM CQ) were included. Test compounds were assayed at 1 mM and data are given in Table 1. Interestingly, the dipeptide spacer was required to block heme polymerization, i.e., while HECINs 9 were not active, HEDICINs 8 displayed variable inhibitory efficiencies, with four out of the twelve compounds (8b, 8e, 8j and 8l) highly active (i.e., comparable to the reference drug, CQ). Though no clear trend could be established regarding stereoelectronic properties of the aryl substituent in compounds 8, it was clear that: (i) hydrogen (i.e., absence of a substituent) or halogens in the para position were detrimental for activity, whereas (ii) nitrogenated groups at either the ortho (8j, o-NO2) or the para (8e, p-NH2; 8l, p-NO2) position of the aryl ring was beneficial, but (iii) detrimental if placed in the meta position (8k, m-NO2). Furthermore, while small alkyl groups in para (8b, p-Me) were advantageous, bulkier groups as in 8c (p-iPr) led to complete loss of activity. Thus, replacement of CQ's aliphatic chain by an adequate dipeptidyl-cinnamoyl moiety as in 8b, 8e, 8j and 8l appears to preserve the parent drug's ability to inhibit hemozoin formation, suggesting that these novel compounds could be promising leads for new CQ surrogates."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01069	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Haemozoin inhibition	50%	%	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	.	.	.	"The capacity of test compounds 8 and 9 to inhibit heme polymerization in vitro was assessed by previously reported methods, given in detail under Experimental. The assays were run in 96-well microplates, where negative controls (water, DMSO) and positive controls (1 mM CQ) were included. Test compounds were assayed at 1 mM and data are given in Table 1. Interestingly, the dipeptide spacer was required to block heme polymerization, i.e., while HECINs 9 were not active, HEDICINs 8 displayed variable inhibitory efficiencies, with four out of the twelve compounds (8b, 8e, 8j and 8l) highly active (i.e., comparable to the reference drug, CQ). Though no clear trend could be established regarding stereoelectronic properties of the aryl substituent in compounds 8, it was clear that: (i) hydrogen (i.e., absence of a substituent) or halogens in the para position were detrimental for activity, whereas (ii) nitrogenated groups at either the ortho (8j, o-NO2) or the para (8e, p-NH2; 8l, p-NO2) position of the aryl ring was beneficial, but (iii) detrimental if placed in the meta position (8k, m-NO2). Furthermore, while small alkyl groups in para (8b, p-Me) were advantageous, bulkier groups as in 8c (p-iPr) led to complete loss of activity. Thus, replacement of CQ's aliphatic chain by an adequate dipeptidyl-cinnamoyl moiety as in 8b, 8e, 8j and 8l appears to preserve the parent drug's ability to inhibit hemozoin formation, suggesting that these novel compounds could be promising leads for new CQ surrogates."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01082	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Haemozoin inhibition	75%	%	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	.	.	.	"The capacity of test compounds 8 and 9 to inhibit heme polymerization in vitro was assessed by previously reported methods, given in detail under Experimental. The assays were run in 96-well microplates, where negative controls (water, DMSO) and positive controls (1 mM CQ) were included. Test compounds were assayed at 1 mM and data are given in Table 1. Interestingly, the dipeptide spacer was required to block heme polymerization, i.e., while HECINs 9 were not active, HEDICINs 8 displayed variable inhibitory efficiencies, with four out of the twelve compounds (8b, 8e, 8j and 8l) highly active (i.e., comparable to the reference drug, CQ). Though no clear trend could be established regarding stereoelectronic properties of the aryl substituent in compounds 8, it was clear that: (i) hydrogen (i.e., absence of a substituent) or halogens in the para position were detrimental for activity, whereas (ii) nitrogenated groups at either the ortho (8j, o-NO2) or the para (8e, p-NH2; 8l, p-NO2) position of the aryl ring was beneficial, but (iii) detrimental if placed in the meta position (8k, m-NO2). Furthermore, while small alkyl groups in para (8b, p-Me) were advantageous, bulkier groups as in 8c (p-iPr) led to complete loss of activity. Thus, replacement of CQ's aliphatic chain by an adequate dipeptidyl-cinnamoyl moiety as in 8b, 8e, 8j and 8l appears to preserve the parent drug's ability to inhibit hemozoin formation, suggesting that these novel compounds could be promising leads for new CQ surrogates."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01080	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	4.89 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum	.	.	48 h	.	.	"Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization. In turn, eleven out of the twelve HEDICINs 8 had IC50 values under 10 &mu;M. Interestingly, three of the four most active HEDICIN blockers of heme polymerization (8b, 8j and 8l) were also among the four most active antiplasmodials, with IC50 below 2 &mu;M. These results suggest that inhibition of heme polymerization is, at least in part, responsible for the anti-plasmodial activity of HEDICINs. An obvious exception to correlation between inhibition of heme polymerization and anti-plasmodial activity in HEDICINs is compound 8c; this bears a bulky electron-donating p-isopropyl group and did not inhibit heme polymerization in vitro, but displayed the highest anti-plasmodial activity. The inability of 8c to inhibit heme polymerization could be related to the bulkiness of the isopropyl group, but due to the higher hydrophobicity of this substituent, 8c was the most lipophilic HEDICIN assayed. Though we could not establish a full correlation between HEDICIN anti-plasmodial activity and estimated clogP values (not shown), the markedly higher lipophilicity of 8c, as compared to the other analogs, could promote a higher permeabilization of this compound into the infected RBC. Kirk and co-workers have demonstrated that P. falciparum parasites create new permeability pathways in host RBC, leading to increased permeability to small organic cations. In summary, though clean correlations could not be drawn between the anti-plasmodial activities displayed by the different HEDICINs (8) in vitro and molecular descriptors such as stereoelectronic factors (aryl substituents) or lipophilicity, it is demonstrated that these compounds displayed anti-plasmodial activity, whereas their HECIN counterparts (9), lacking the dipeptide spacer, did not. HEDICINs (8) inhibited heme polymerization in vitro, suggesting that this inhibitory activity is at least in part responsible for their anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01084	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	8 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum	.	.	48 h	.	.	"Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization. In turn, eleven out of the twelve HEDICINs 8 had IC50 values under 10 &mu;M. Interestingly, three of the four most active HEDICIN blockers of heme polymerization (8b, 8j and 8l) were also among the four most active antiplasmodials, with IC50 below 2 &mu;M. These results suggest that inhibition of heme polymerization is, at least in part, responsible for the anti-plasmodial activity of HEDICINs. An obvious exception to correlation between inhibition of heme polymerization and anti-plasmodial activity in HEDICINs is compound 8c; this bears a bulky electron-donating p-isopropyl group and did not inhibit heme polymerization in vitro, but displayed the highest anti-plasmodial activity. The inability of 8c to inhibit heme polymerization could be related to the bulkiness of the isopropyl group, but due to the higher hydrophobicity of this substituent, 8c was the most lipophilic HEDICIN assayed. Though we could not establish a full correlation between HEDICIN anti-plasmodial activity and estimated clogP values (not shown), the markedly higher lipophilicity of 8c, as compared to the other analogs, could promote a higher permeabilization of this compound into the infected RBC. Kirk and co-workers have demonstrated that P. falciparum parasites create new permeability pathways in host RBC, leading to increased permeability to small organic cations. In summary, though clean correlations could not be drawn between the anti-plasmodial activities displayed by the different HEDICINs (8) in vitro and molecular descriptors such as stereoelectronic factors (aryl substituents) or lipophilicity, it is demonstrated that these compounds displayed anti-plasmodial activity, whereas their HECIN counterparts (9), lacking the dipeptide spacer, did not. HEDICINs (8) inhibited heme polymerization in vitro, suggesting that this inhibitory activity is at least in part responsible for their anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01079	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1.96 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum	.	.	48 h	.	.	"Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization. In turn, eleven out of the twelve HEDICINs 8 had IC50 values under 10 &mu;M. Interestingly, three of the four most active HEDICIN blockers of heme polymerization (8b, 8j and 8l) were also among the four most active antiplasmodials, with IC50 below 2 &mu;M. These results suggest that inhibition of heme polymerization is, at least in part, responsible for the anti-plasmodial activity of HEDICINs. An obvious exception to correlation between inhibition of heme polymerization and anti-plasmodial activity in HEDICINs is compound 8c; this bears a bulky electron-donating p-isopropyl group and did not inhibit heme polymerization in vitro, but displayed the highest anti-plasmodial activity. The inability of 8c to inhibit heme polymerization could be related to the bulkiness of the isopropyl group, but due to the higher hydrophobicity of this substituent, 8c was the most lipophilic HEDICIN assayed. Though we could not establish a full correlation between HEDICIN anti-plasmodial activity and estimated clogP values (not shown), the markedly higher lipophilicity of 8c, as compared to the other analogs, could promote a higher permeabilization of this compound into the infected RBC. Kirk and co-workers have demonstrated that P. falciparum parasites create new permeability pathways in host RBC, leading to increased permeability to small organic cations. In summary, though clean correlations could not be drawn between the anti-plasmodial activities displayed by the different HEDICINs (8) in vitro and molecular descriptors such as stereoelectronic factors (aryl substituents) or lipophilicity, it is demonstrated that these compounds displayed anti-plasmodial activity, whereas their HECIN counterparts (9), lacking the dipeptide spacer, did not. HEDICINs (8) inhibited heme polymerization in vitro, suggesting that this inhibitory activity is at least in part responsible for their anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01078	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.83 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum	.	.	48 h	.	.	"Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization. In turn, eleven out of the twelve HEDICINs 8 had IC50 values under 10 &mu;M. Interestingly, three of the four most active HEDICIN blockers of heme polymerization (8b, 8j and 8l) were also among the four most active antiplasmodials, with IC50 below 2 &mu;M. These results suggest that inhibition of heme polymerization is, at least in part, responsible for the anti-plasmodial activity of HEDICINs. An obvious exception to correlation between inhibition of heme polymerization and anti-plasmodial activity in HEDICINs is compound 8c; this bears a bulky electron-donating p-isopropyl group and did not inhibit heme polymerization in vitro, but displayed the highest anti-plasmodial activity. The inability of 8c to inhibit heme polymerization could be related to the bulkiness of the isopropyl group, but due to the higher hydrophobicity of this substituent, 8c was the most lipophilic HEDICIN assayed. Though we could not establish a full correlation between HEDICIN anti-plasmodial activity and estimated clogP values (not shown), the markedly higher lipophilicity of 8c, as compared to the other analogs, could promote a higher permeabilization of this compound into the infected RBC. Kirk and co-workers have demonstrated that P. falciparum parasites create new permeability pathways in host RBC, leading to increased permeability to small organic cations. In summary, though clean correlations could not be drawn between the anti-plasmodial activities displayed by the different HEDICINs (8) in vitro and molecular descriptors such as stereoelectronic factors (aryl substituents) or lipophilicity, it is demonstrated that these compounds displayed anti-plasmodial activity, whereas their HECIN counterparts (9), lacking the dipeptide spacer, did not. HEDICINs (8) inhibited heme polymerization in vitro, suggesting that this inhibitory activity is at least in part responsible for their anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01077	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10.8 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum	.	.	48 h	.	.	"Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization. In turn, eleven out of the twelve HEDICINs 8 had IC50 values under 10 &mu;M. Interestingly, three of the four most active HEDICIN blockers of heme polymerization (8b, 8j and 8l) were also among the four most active antiplasmodials, with IC50 below 2 &mu;M. These results suggest that inhibition of heme polymerization is, at least in part, responsible for the anti-plasmodial activity of HEDICINs. An obvious exception to correlation between inhibition of heme polymerization and anti-plasmodial activity in HEDICINs is compound 8c; this bears a bulky electron-donating p-isopropyl group and did not inhibit heme polymerization in vitro, but displayed the highest anti-plasmodial activity. The inability of 8c to inhibit heme polymerization could be related to the bulkiness of the isopropyl group, but due to the higher hydrophobicity of this substituent, 8c was the most lipophilic HEDICIN assayed. Though we could not establish a full correlation between HEDICIN anti-plasmodial activity and estimated clogP values (not shown), the markedly higher lipophilicity of 8c, as compared to the other analogs, could promote a higher permeabilization of this compound into the infected RBC. Kirk and co-workers have demonstrated that P. falciparum parasites create new permeability pathways in host RBC, leading to increased permeability to small organic cations. In summary, though clean correlations could not be drawn between the anti-plasmodial activities displayed by the different HEDICINs (8) in vitro and molecular descriptors such as stereoelectronic factors (aryl substituents) or lipophilicity, it is demonstrated that these compounds displayed anti-plasmodial activity, whereas their HECIN counterparts (9), lacking the dipeptide spacer, did not. HEDICINs (8) inhibited heme polymerization in vitro, suggesting that this inhibitory activity is at least in part responsible for their anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01083	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	3.28 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum	.	.	48 h	.	.	"Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization. In turn, eleven out of the twelve HEDICINs 8 had IC50 values under 10 &mu;M. Interestingly, three of the four most active HEDICIN blockers of heme polymerization (8b, 8j and 8l) were also among the four most active antiplasmodials, with IC50 below 2 &mu;M. These results suggest that inhibition of heme polymerization is, at least in part, responsible for the anti-plasmodial activity of HEDICINs. An obvious exception to correlation between inhibition of heme polymerization and anti-plasmodial activity in HEDICINs is compound 8c; this bears a bulky electron-donating p-isopropyl group and did not inhibit heme polymerization in vitro, but displayed the highest anti-plasmodial activity. The inability of 8c to inhibit heme polymerization could be related to the bulkiness of the isopropyl group, but due to the higher hydrophobicity of this substituent, 8c was the most lipophilic HEDICIN assayed. Though we could not establish a full correlation between HEDICIN anti-plasmodial activity and estimated clogP values (not shown), the markedly higher lipophilicity of 8c, as compared to the other analogs, could promote a higher permeabilization of this compound into the infected RBC. Kirk and co-workers have demonstrated that P. falciparum parasites create new permeability pathways in host RBC, leading to increased permeability to small organic cations. In summary, though clean correlations could not be drawn between the anti-plasmodial activities displayed by the different HEDICINs (8) in vitro and molecular descriptors such as stereoelectronic factors (aryl substituents) or lipophilicity, it is demonstrated that these compounds displayed anti-plasmodial activity, whereas their HECIN counterparts (9), lacking the dipeptide spacer, did not. HEDICINs (8) inhibited heme polymerization in vitro, suggesting that this inhibitory activity is at least in part responsible for their anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01076	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	5.43 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum	.	.	48 h	.	.	"Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization. In turn, eleven out of the twelve HEDICINs 8 had IC50 values under 10 &mu;M. Interestingly, three of the four most active HEDICIN blockers of heme polymerization (8b, 8j and 8l) were also among the four most active antiplasmodials, with IC50 below 2 &mu;M. These results suggest that inhibition of heme polymerization is, at least in part, responsible for the anti-plasmodial activity of HEDICINs. An obvious exception to correlation between inhibition of heme polymerization and anti-plasmodial activity in HEDICINs is compound 8c; this bears a bulky electron-donating p-isopropyl group and did not inhibit heme polymerization in vitro, but displayed the highest anti-plasmodial activity. The inability of 8c to inhibit heme polymerization could be related to the bulkiness of the isopropyl group, but due to the higher hydrophobicity of this substituent, 8c was the most lipophilic HEDICIN assayed. Though we could not establish a full correlation between HEDICIN anti-plasmodial activity and estimated clogP values (not shown), the markedly higher lipophilicity of 8c, as compared to the other analogs, could promote a higher permeabilization of this compound into the infected RBC. Kirk and co-workers have demonstrated that P. falciparum parasites create new permeability pathways in host RBC, leading to increased permeability to small organic cations. In summary, though clean correlations could not be drawn between the anti-plasmodial activities displayed by the different HEDICINs (8) in vitro and molecular descriptors such as stereoelectronic factors (aryl substituents) or lipophilicity, it is demonstrated that these compounds displayed anti-plasmodial activity, whereas their HECIN counterparts (9), lacking the dipeptide spacer, did not. HEDICINs (8) inhibited heme polymerization in vitro, suggesting that this inhibitory activity is at least in part responsible for their anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01075	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	4.67 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum	.	.	48 h	.	.	"Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization. In turn, eleven out of the twelve HEDICINs 8 had IC50 values under 10 &mu;M. Interestingly, three of the four most active HEDICIN blockers of heme polymerization (8b, 8j and 8l) were also among the four most active antiplasmodials, with IC50 below 2 &mu;M. These results suggest that inhibition of heme polymerization is, at least in part, responsible for the anti-plasmodial activity of HEDICINs. An obvious exception to correlation between inhibition of heme polymerization and anti-plasmodial activity in HEDICINs is compound 8c; this bears a bulky electron-donating p-isopropyl group and did not inhibit heme polymerization in vitro, but displayed the highest anti-plasmodial activity. The inability of 8c to inhibit heme polymerization could be related to the bulkiness of the isopropyl group, but due to the higher hydrophobicity of this substituent, 8c was the most lipophilic HEDICIN assayed. Though we could not establish a full correlation between HEDICIN anti-plasmodial activity and estimated clogP values (not shown), the markedly higher lipophilicity of 8c, as compared to the other analogs, could promote a higher permeabilization of this compound into the infected RBC. Kirk and co-workers have demonstrated that P. falciparum parasites create new permeability pathways in host RBC, leading to increased permeability to small organic cations. In summary, though clean correlations could not be drawn between the anti-plasmodial activities displayed by the different HEDICINs (8) in vitro and molecular descriptors such as stereoelectronic factors (aryl substituents) or lipophilicity, it is demonstrated that these compounds displayed anti-plasmodial activity, whereas their HECIN counterparts (9), lacking the dipeptide spacer, did not. HEDICINs (8) inhibited heme polymerization in vitro, suggesting that this inhibitory activity is at least in part responsible for their anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01074	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	2.89 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum	.	.	48 h	.	.	"Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization. In turn, eleven out of the twelve HEDICINs 8 had IC50 values under 10 &mu;M. Interestingly, three of the four most active HEDICIN blockers of heme polymerization (8b, 8j and 8l) were also among the four most active antiplasmodials, with IC50 below 2 &mu;M. These results suggest that inhibition of heme polymerization is, at least in part, responsible for the anti-plasmodial activity of HEDICINs. An obvious exception to correlation between inhibition of heme polymerization and anti-plasmodial activity in HEDICINs is compound 8c; this bears a bulky electron-donating p-isopropyl group and did not inhibit heme polymerization in vitro, but displayed the highest anti-plasmodial activity. The inability of 8c to inhibit heme polymerization could be related to the bulkiness of the isopropyl group, but due to the higher hydrophobicity of this substituent, 8c was the most lipophilic HEDICIN assayed. Though we could not establish a full correlation between HEDICIN anti-plasmodial activity and estimated clogP values (not shown), the markedly higher lipophilicity of 8c, as compared to the other analogs, could promote a higher permeabilization of this compound into the infected RBC. Kirk and co-workers have demonstrated that P. falciparum parasites create new permeability pathways in host RBC, leading to increased permeability to small organic cations. In summary, though clean correlations could not be drawn between the anti-plasmodial activities displayed by the different HEDICINs (8) in vitro and molecular descriptors such as stereoelectronic factors (aryl substituents) or lipophilicity, it is demonstrated that these compounds displayed anti-plasmodial activity, whereas their HECIN counterparts (9), lacking the dipeptide spacer, did not. HEDICINs (8) inhibited heme polymerization in vitro, suggesting that this inhibitory activity is at least in part responsible for their anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01073	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	2.55 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum	.	.	48 h	.	.	"Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization. In turn, eleven out of the twelve HEDICINs 8 had IC50 values under 10 &mu;M. Interestingly, three of the four most active HEDICIN blockers of heme polymerization (8b, 8j and 8l) were also among the four most active antiplasmodials, with IC50 below 2 &mu;M. These results suggest that inhibition of heme polymerization is, at least in part, responsible for the anti-plasmodial activity of HEDICINs. An obvious exception to correlation between inhibition of heme polymerization and anti-plasmodial activity in HEDICINs is compound 8c; this bears a bulky electron-donating p-isopropyl group and did not inhibit heme polymerization in vitro, but displayed the highest anti-plasmodial activity. The inability of 8c to inhibit heme polymerization could be related to the bulkiness of the isopropyl group, but due to the higher hydrophobicity of this substituent, 8c was the most lipophilic HEDICIN assayed. Though we could not establish a full correlation between HEDICIN anti-plasmodial activity and estimated clogP values (not shown), the markedly higher lipophilicity of 8c, as compared to the other analogs, could promote a higher permeabilization of this compound into the infected RBC. Kirk and co-workers have demonstrated that P. falciparum parasites create new permeability pathways in host RBC, leading to increased permeability to small organic cations. In summary, though clean correlations could not be drawn between the anti-plasmodial activities displayed by the different HEDICINs (8) in vitro and molecular descriptors such as stereoelectronic factors (aryl substituents) or lipophilicity, it is demonstrated that these compounds displayed anti-plasmodial activity, whereas their HECIN counterparts (9), lacking the dipeptide spacer, did not. HEDICINs (8) inhibited heme polymerization in vitro, suggesting that this inhibitory activity is at least in part responsible for their anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01072	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1.66 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum	.	.	48 h	.	.	"Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization. In turn, eleven out of the twelve HEDICINs 8 had IC50 values under 10 &mu;M. Interestingly, three of the four most active HEDICIN blockers of heme polymerization (8b, 8j and 8l) were also among the four most active antiplasmodials, with IC50 below 2 &mu;M. These results suggest that inhibition of heme polymerization is, at least in part, responsible for the anti-plasmodial activity of HEDICINs. An obvious exception to correlation between inhibition of heme polymerization and anti-plasmodial activity in HEDICINs is compound 8c; this bears a bulky electron-donating p-isopropyl group and did not inhibit heme polymerization in vitro, but displayed the highest anti-plasmodial activity. The inability of 8c to inhibit heme polymerization could be related to the bulkiness of the isopropyl group, but due to the higher hydrophobicity of this substituent, 8c was the most lipophilic HEDICIN assayed. Though we could not establish a full correlation between HEDICIN anti-plasmodial activity and estimated clogP values (not shown), the markedly higher lipophilicity of 8c, as compared to the other analogs, could promote a higher permeabilization of this compound into the infected RBC. Kirk and co-workers have demonstrated that P. falciparum parasites create new permeability pathways in host RBC, leading to increased permeability to small organic cations. In summary, though clean correlations could not be drawn between the anti-plasmodial activities displayed by the different HEDICINs (8) in vitro and molecular descriptors such as stereoelectronic factors (aryl substituents) or lipophilicity, it is demonstrated that these compounds displayed anti-plasmodial activity, whereas their HECIN counterparts (9), lacking the dipeptide spacer, did not. HEDICINs (8) inhibited heme polymerization in vitro, suggesting that this inhibitory activity is at least in part responsible for their anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01069	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	2.1 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum	.	.	48 h	.	.	"Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization. In turn, eleven out of the twelve HEDICINs 8 had IC50 values under 10 &mu;M. Interestingly, three of the four most active HEDICIN blockers of heme polymerization (8b, 8j and 8l) were also among the four most active antiplasmodials, with IC50 below 2 &mu;M. These results suggest that inhibition of heme polymerization is, at least in part, responsible for the anti-plasmodial activity of HEDICINs. An obvious exception to correlation between inhibition of heme polymerization and anti-plasmodial activity in HEDICINs is compound 8c; this bears a bulky electron-donating p-isopropyl group and did not inhibit heme polymerization in vitro, but displayed the highest anti-plasmodial activity. The inability of 8c to inhibit heme polymerization could be related to the bulkiness of the isopropyl group, but due to the higher hydrophobicity of this substituent, 8c was the most lipophilic HEDICIN assayed. Though we could not establish a full correlation between HEDICIN anti-plasmodial activity and estimated clogP values (not shown), the markedly higher lipophilicity of 8c, as compared to the other analogs, could promote a higher permeabilization of this compound into the infected RBC. Kirk and co-workers have demonstrated that P. falciparum parasites create new permeability pathways in host RBC, leading to increased permeability to small organic cations. In summary, though clean correlations could not be drawn between the anti-plasmodial activities displayed by the different HEDICINs (8) in vitro and molecular descriptors such as stereoelectronic factors (aryl substituents) or lipophilicity, it is demonstrated that these compounds displayed anti-plasmodial activity, whereas their HECIN counterparts (9), lacking the dipeptide spacer, did not. HEDICINs (8) inhibited heme polymerization in vitro, suggesting that this inhibitory activity is at least in part responsible for their anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01082	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1.23 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum	.	.	48 h	.	.	"Activity against blood-stage CQ-resistant P. falciparum strain W2 was assessed as previously reported and given in detail in Experimental. Results demonstrated a complete lack of activity displayed by HECINs 9, correlating with their inability to inhibit heme polymerization. In turn, eleven out of the twelve HEDICINs 8 had IC50 values under 10 &mu;M. Interestingly, three of the four most active HEDICIN blockers of heme polymerization (8b, 8j and 8l) were also among the four most active antiplasmodials, with IC50 below 2 &mu;M. These results suggest that inhibition of heme polymerization is, at least in part, responsible for the anti-plasmodial activity of HEDICINs. An obvious exception to correlation between inhibition of heme polymerization and anti-plasmodial activity in HEDICINs is compound 8c; this bears a bulky electron-donating p-isopropyl group and did not inhibit heme polymerization in vitro, but displayed the highest anti-plasmodial activity. The inability of 8c to inhibit heme polymerization could be related to the bulkiness of the isopropyl group, but due to the higher hydrophobicity of this substituent, 8c was the most lipophilic HEDICIN assayed. Though we could not establish a full correlation between HEDICIN anti-plasmodial activity and estimated clogP values (not shown), the markedly higher lipophilicity of 8c, as compared to the other analogs, could promote a higher permeabilization of this compound into the infected RBC. Kirk and co-workers have demonstrated that P. falciparum parasites create new permeability pathways in host RBC, leading to increased permeability to small organic cations. In summary, though clean correlations could not be drawn between the anti-plasmodial activities displayed by the different HEDICINs (8) in vitro and molecular descriptors such as stereoelectronic factors (aryl substituents) or lipophilicity, it is demonstrated that these compounds displayed anti-plasmodial activity, whereas their HECIN counterparts (9), lacking the dipeptide spacer, did not. HEDICINs (8) inhibited heme polymerization in vitro, suggesting that this inhibitory activity is at least in part responsible for their anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01080	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	19.6 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01084	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01079	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01078	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01077	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01083	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	20.3 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01076	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	23.1 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01075	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01074	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01073	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	48.3 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01072	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01069	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	28.1 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01082	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01080	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01083	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01076	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01073	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00571	PDC_01069	Malaria	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Plasmodium falciparum infection	Plasmodium falciparum strain W2	.	.	30 min	.	.	"The very different activities of compounds 8 and 9 suggest that the retro-enantio dipeptide spacer has a relevant role in determining anti-plasmodial activity. In view of this, we hypothesized that the anti-plasmodial activity of HEDICINs could also be partly due to falcipain inhibition. Therefore, both HEDICINs 8 and HECINs 9 were evaluated in vitro for inhibition of falcipains, using previously described methods, given in detail under Experimental. Only those compounds with IC50 < 50 &mu;M against FP2 were assayed against FP3, as it has been established that FP2 has a larger catalytic cavity that accommodates a wider range of inhibitors than FP3. Consistent with this assumption, none of the compounds that inhibited FP2 in vitro displayed IC50 < 50 &mu;M against FP3. Falcipain inhibition results contrasted with those for inhibition of heme polymerization or parasite development. HECINs 9 generally displayed more potent inhibition of falcipain than did HEDICINs 8. The ability of the test compounds to inhibit FP2 did not correlate with their anti-plasmodial activity. Although none of the HECINs 9 displayed anti-plasmodial activity, many inhibited FP2 and one of them, 9j, was actually the best FP2 inhibitor amongst the test compounds. Concerning HEDICINs, 8a, 8f and 8k, derived from cinnamic acid, m-fluorocinnamic acid, and m-nitrocinnamic acid, respectively, were the most active HEDICINs against FP2, with IC50 values of 19.7, 23.1 and 28.1 &mu;M. Thus, stereoelectronic effects from aryl substituents did not correlate with inhibitory activities, as in HEDICINs 8 the most active compound was unsubstituted (8a), followed by the meta-fluorinated compound (8f); in turn, in HECINs 9, the meta-fluorinated derivative was inactive, whereas the most active of the set was 9j, which bears a meta-nitro substituent. The effect of amino acid configuration on HEDICIN activity was also assessed through synthesis and evaluation of 10a, the L-amino acid analog of 8a; interestingly, replacement of the D-amino acids by their natural L counterparts led to a clear decrease in both anti-plasmodial and falcipain-inhibitory activity. Therefore, amino acid configuration does influence compound behavior as either anti-plasmodial agent or falcipain inhibitor and, in the particular case of HEDICINs, data suggests that D-amino acids are preferable. Of note, the compound with highest anti-plasmodial activity, 8c, was completely devoid of inhibitory activity against FP2. This compound likely exerts its anti-plasmodial action by mechanisms other than inhibition of hemozoin formation or falcipain activity. Data on compound 8e reinforce the idea that falcipain or hemozoin inhibition are not the main mechanisms of action responsible for HEDICINs anti-plasmodial activity: 8e, bearing a p-amino substituent in the aryl ring, was the test compound which best reached our original goal of a dual-action inhibitor, by joining high hemozoin inhibitory activity with an IC50 20 &mu;M against FP2; however, such was not translated into the highest anti-plasmodial activity being observed for 8e. Taken together, data from in vitro falcipain inhibition and parasite development assays suggest that the dipeptide spacer in HEDICINs 8 promotes uptake into infected RBCs. This hypothesis could explain why HEDICINs perform better than HECINs as antiplasmodials, despite the observation that HECINs were better falcipain-inhibitors than the HEDICINs. In addition, lipophilicity could have a role in compound uptake and anti-plasmodial action, as HEDICINs 8 are more lipophilic than HECINs 9 (due to the D-Leu and the D-hPhe hydrophobic side chains), and the most lipophilic compound, 8c, had the greatest anti-plasmodial activity."	"HEterocyclic-DIpeptide-CINnamic acid conjugates (HEDICINs) were designed to link, through a suitable spacer, (i) the CQ heterocyclic core, known as relevant to inhibit hemozoin formation, to a (ii) trans-cinnamic acid motif, as cinnamic acids have been described to exhibit both antimalarial activity and inhibiting enzyme catalytic Cys residues. Cinnamic acid derivatives, due to their a,&beta;-unsaturated carbonyl moiety, can act as Michael acceptors and inhibit cysteine proteases through S-alkylation. Irreversible S-alkylation of the falcipain catalytic Cys has been considered the major mechanism behind the inhibitory and in vitro anti-plasmodial activity of peptidyl inhibitors including leupeptin and vinyl sulfones developed by Rosenthal and co-workers. The most active vinyl sulfones contained a dipeptide Leu-hPhe spacer between a bulky moiety and the S-alkylating motif. Unfortunately, peptide-based inhibitors are prone to proteolytic degradation, a problem that can be overcome by use of suitable peptide delivery systems. Still, such systems are likely to impair efficient inhibition of the target enzyme. One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases. The retro-enantio analog of Leu-hPhe seems the best mimic of falcipain P2-P1 sites, linking the putative P3 motif (heterocyclic core of CQ) to the Michael acceptor in P1 (cinnamic acid). However, preliminary computational studies by our group on HEDICINs 1 and 8f (structures given below, Fig. 2A and B, respectively), differing only in the order of the two D-amino acids, suggested that the inverse sequence, i.e., D-hPhe-D-Leu, would allow a closer approximation of the electrophilic moiety to the catalytic center. These preliminary observations in silico were later supported in vitro by anti-plasmodial activity tests against the CQ-resistant Plasmodium falciparum strain W2, which revealed that 1 did not display any antimalarial activity up to 10 &mu;M, while 8f inhibited parasite development with an IC50 of 5.43 &mu;M. Therefore, we engaged in the synthesis of HEDICINs with general structure 8 as potential dual-action drugs against blood-stage parasites. Analogs lacking the dipeptide spacer, HECINs 9, were also prepared to assess the relevance of that spacer. Compounds 8 and 9 were evaluated in vitro concerning their ability to inhibit (i) heme polymerization to hemozoin; (ii) falcipain activity; and (iii) development of blood-stage P. falciparum. In order to support observed SAR and to rationalize the activity profile of the novel compounds, we also performed molecular modeling calculations on computational models derived from X-ray structures of FP2 (PDB code: 3BPF) and FP3 (PDB code: 3BWK) co-crystalized with E64 and K11017, respectively."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	48.25 &plusmn; 45.02%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01128	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	10.36 &plusmn; 22.24%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01127	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	23.17 &plusmn; 25.32%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01126	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	39.47 &plusmn; 25.44%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01125	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	37.58 &plusmn; 20.23%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01124	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	31.34 &plusmn; 31.32%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01123	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	33.01 &plusmn; 38.16%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01122	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	35.05 &plusmn; 29.27%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01121	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	30.75 &plusmn; 24.24%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01120	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	37.25 &plusmn; 21.12%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	44.27 &plusmn; 42.46%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01118	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	41.83 &plusmn; 39.35%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01117	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	21.24 &plusmn; 15.74%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01116	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	30.56 &plusmn; 21.46%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01115	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	35.75 &plusmn; 30.35%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01114	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	38.16 &plusmn; 19.26%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01113	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	22.17 &plusmn; 28.57%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01112	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	18.24 &plusmn; 11.56%	%	.	.	.	.	.	.	.	.	30min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	59.37 &plusmn; 37.02%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01128	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	40.78 &plusmn; 32.03%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01127	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	49.74 &plusmn; 35.11%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01126	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	45.77 &plusmn; 26.32%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01125	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	48.23 &plusmn; 14.23%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01124	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	37.20 &plusmn; 15.13%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01123	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	38.01 &plusmn; 29.23%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01122	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	36.45 &plusmn; 27.36%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01121	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	38.20 &plusmn; 32.09%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01120	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	32.19 &plusmn; 14.78%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	52.22 &plusmn; 33.12%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01118	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	47.33 &plusmn; 19.47%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01117	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	45.23 &plusmn; 11.14%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01116	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	42.32 &plusmn; 16.41%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01115	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	41.18 &plusmn; 17.45%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01114	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	35.13 &plusmn; 22.25%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01113	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	28.12 &plusmn; 19.81%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01112	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	17.23 &plusmn; 13.55%	%	.	.	.	.	.	.	.	.	60min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	44.67 &plusmn; 41.08%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01128	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	46.45 &plusmn; 5.46%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01127	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	21.35 &plusmn; 27.20%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01126	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	47.36 &plusmn; 28.21%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01125	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	46.48 &plusmn; 9.15%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01124	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	40.56 &plusmn; 8.32%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01123	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	41.23 &plusmn; 44.46%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01122	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	35.19 &plusmn; 21.33%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01121	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	40.36 &plusmn; 23.49%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01120	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	22.23 &plusmn; 14.66%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	54.39 &plusmn; 23.67%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01118	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	51.25 &plusmn; 11.84%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01117	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	34.56 &plusmn; 35.77%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01116	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	44.13 &plusmn; 28.22%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01115	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	43.23 &plusmn; 32.49%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01114	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	46.08 &plusmn; 19.94%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01113	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	34.55 &plusmn; 13.29%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01112	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	29.25 &plusmn; 17.12%	%	.	.	.	.	.	.	.	.	90min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	34.55 &plusmn; 38.43%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01128	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	49.09 &plusmn; 29.03%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01127	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	18.79 &plusmn; 15.74%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01126	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	35.79 &plusmn; 9.32%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01125	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	42.03 &plusmn; 6.41%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01124	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	45.46 &plusmn; 23.54%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01123	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	27.32 &plusmn; 14.88%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01122	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	28.55 &plusmn; 12.36%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01121	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	42.43 &plusmn; 27.22%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01120	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	39.38 &plusmn; 13.48%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	41.28 &plusmn; 13.33%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01118	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	32.33 &plusmn; 22.89%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01117	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	39.25 &plusmn; 17.48%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01116	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	38.45 &plusmn; 19.66%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01115	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	30.25 &plusmn; 31.49%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01114	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	37.12 &plusmn; 15.25%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01113	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	40.67 &plusmn; 33.57%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01112	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	39.23 &plusmn; 17.12%	%	.	.	.	.	.	.	.	.	120min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	25.46 &plusmn; 12.12%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01128	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	22.37 &plusmn; 34.30%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01127	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	25.05 &plusmn; 18.13%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01126	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	25.88 &plusmn; 11.77%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01125	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	28.79 &plusmn; 10.13%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01124	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	21.12 &plusmn; 14.45%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01123	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	15.25 &plusmn; 22.46%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01122	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	16.69 &plusmn; 10.33%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01121	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	23.19 &plusmn; 15.36%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01120	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	24.33 &plusmn; 6.49%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	29.04 &plusmn; 22.58%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01118	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	18.32 &plusmn; 37.12%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01117	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	22.12 &plusmn; 26.22%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01116	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	26.47 &plusmn; 27.55%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01115	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	28.87 &plusmn; 21.93%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01114	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	29.38 &plusmn; 16.45%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01113	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	13.54 &plusmn; 18.46%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01112	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	12.25 &plusmn; 26.18%	%	.	.	.	.	.	.	.	.	150min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	18.86 &plusmn; 19.46%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01128	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	14.36 &plusmn; 28.12%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01127	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	15.68 &plusmn; 11.32%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01126	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	16.03 &plusmn; 8.96%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01125	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	19.22 &plusmn; 17.46%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01124	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	15.32 &plusmn; 11.18%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01123	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	16.13 &plusmn; 13.39%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01122	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	14.23 &plusmn; 12.18%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01121	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	19.25 &plusmn; 14.39%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01120	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	13.29 &plusmn; 12.47%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	25.69 &plusmn; 11.36%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01118	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	22.45 &plusmn; 43.22%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01117	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	19.45 &plusmn; 21.79%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01116	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	25.07 &plusmn; 11.21%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01115	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	20.94 &plusmn; 14.46%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01114	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	21.55 &plusmn; 17.29%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01113	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	18.77 &plusmn; 13.45%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01112	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	12.32 &plusmn; 14.94%	%	.	.	.	.	.	.	.	.	180min	0.15mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.29 &plusmn; 0.35 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01128	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	2.05 &plusmn; 0.76 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01127	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.73 &plusmn; 0.31 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01126	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.85 &plusmn; 0.54 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01125	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.55 &plusmn; 0.43 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01124	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.70 &plusmn; 0.41 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01123	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.43 &plusmn; 0.38 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01122	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.59 &plusmn; 0.44 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01121	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.62 &plusmn; 0.43 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01120	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.39 &plusmn; 0.28 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.47 &plusmn; 0.27 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01118	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.89 &plusmn; 0.60 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01117	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.45 &plusmn; 0.42 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01116	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.78 &plusmn; 0.35 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01115	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.61 &plusmn; 0.32 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01114	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.41 &plusmn; 0.49 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01113	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.97 &plusmn; 0.53 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01112	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	2.35 &plusmn; 0.55 mg	mg	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	60.70%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01128	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	37.50%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01127	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	47.30%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01126	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	43.60%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01125	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	52.70%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01124	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	48.20%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01123	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	56.40%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01122	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	51.50%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01121	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	50.60%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01120	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	57.60%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	55.20%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01118	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	42.40%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01117	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	55.80%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01116	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	45.70%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01115	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	50.90%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01114	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	57%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01113	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	40%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01112	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	28.40%	%	.	.	.	.	.	.	.	.	30 min	0.15mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.65 &plusmn; 0.51 mg	mg	.	.	.	.	.	.	.	.	30 min	0.1 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	2.01 &plusmn; 0.48 mg	mg	.	.	.	.	.	.	.	.	30 min	0.05 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01125	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.81 &plusmn; 0.38 mg	mg	.	.	.	.	.	.	.	.	30 min	0.1 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01125	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	2.21 &plusmn; 0.47 mg	mg	.	.	.	.	.	.	.	.	30 min	0.05 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	1.79 &plusmn; 0.54 mg	mg	.	.	.	.	.	.	.	.	30 min	0.1 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	2.35 &plusmn; 0.43 mg	mg	.	.	.	.	.	.	.	.	30 min	0.05 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01115	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	2.20 &plusmn; 0.43 mg	mg	.	.	.	.	.	.	.	.	30 min	0.1 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01115	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	2.75 &plusmn; 0.66 mg	mg	.	.	.	.	.	.	.	.	30 min	0.05 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01114	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	2.41 &plusmn; 0.58 mg	mg	.	.	.	.	.	.	.	.	30 min	0.1 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01114	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema weight	2.91 &plusmn; 0.67 mg	mg	.	.	.	.	.	.	.	.	30 min	0.05 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	49.60%	%	.	.	.	.	.	.	.	.	30 min	0.1 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	38.70%	%	.	.	.	.	.	.	.	.	30 min	0.05 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01125	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	44.80%	%	.	.	.	.	.	.	.	.	30 min	0.1 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01125	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	32.60%	%	.	.	.	.	.	.	.	.	30 min	0.05 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	45.40%	%	.	.	.	.	.	.	.	.	30 min	0.1 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	28.30%	%	.	.	.	.	.	.	.	.	30 min	0.05 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01115	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	32.90%	%	.	.	.	.	.	.	.	.	30 min	0.1 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01115	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	16.20%	%	.	.	.	.	.	.	.	.	30 min	0.05 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01114	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	26.50%	%	.	.	.	.	.	.	.	.	30 min	0.1 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01114	Mesenteric ischemia and reperfusion injury	Male ICR mice xylene-induced ear edema model.	Obtained from the Model Organism Data	.	Edema inhibition rate	11.30%	%	.	.	.	.	.	.	.	.	30 min	0.05 mmol/kg	.	"All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	35.41 &plusmn; 13.56%	%	.	.	.	.	.	.	.	.	30min	0.10mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	29.22 &plusmn; 10.26%	%	.	.	.	.	.	.	.	.	30min	0.05mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	32.32 &plusmn; 19.55%	%	.	.	.	.	.	.	.	.	30min	0.10mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	11.55 &plusmn; 9.28%	%	.	.	.	.	.	.	.	.	30min	0.05mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	37.65 &plusmn; 28.53%	%	.	.	.	.	.	.	.	.	60min	0.10mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	23.45 &plusmn; 15.31%	%	.	.	.	.	.	.	.	.	60min	0.05mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	34.48 &plusmn; 21.03%	%	.	.	.	.	.	.	.	.	60min	0.10mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	26.54 &plusmn; 10.33%	%	.	.	.	.	.	.	.	.	60min	0.05mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	32.73 &plusmn; 18.69%	%	.	.	.	.	.	.	.	.	90min	0.10mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	20.65 &plusmn; 18.94%	%	.	.	.	.	.	.	.	.	90min	0.05mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	38.33 &plusmn; 11.25%	%	.	.	.	.	.	.	.	.	90min	0.10mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	23.58 &plusmn; 11.46%	%	.	.	.	.	.	.	.	.	90min	0.05mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	25.45 &plusmn; 15.37%	%	.	.	.	.	.	.	.	.	120min	0.10mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	17.97 &plusmn; 14.64%	%	.	.	.	.	.	.	.	.	120min	0.05mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	23.08 &plusmn; 13.89%	%	.	.	.	.	.	.	.	.	120min	0.10mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	18.99 &plusmn; 8.96%	%	.	.	.	.	.	.	.	.	120min	0.05mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	22.13 &plusmn; 14.89%	%	.	.	.	.	.	.	.	.	150min	0.10mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	8.23 &plusmn; 12.04%	%	.	.	.	.	.	.	.	.	150min	0.05mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	21.39 &plusmn; 15.60%	%	.	.	.	.	.	.	.	.	150min	0.10mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	15.43 &plusmn; 10.94%	%	.	.	.	.	.	.	.	.	150min	0.05mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	13.42 &plusmn; 8.68%	%	.	.	.	.	.	.	.	.	180min	0.10mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01129	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	7.46 &plusmn; 8.95%	%	.	.	.	.	.	.	.	.	180min	0.05mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	14.38 &plusmn; 20.13%	%	.	.	.	.	.	.	.	.	180min	0.10mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00607	PDC_01119	Mesenteric ischemia and reperfusion injury	Male ICR mice.	Obtained from the Model Organism Data	.	Pain threshold variation	9.06 &plusmn; 15.43%	%	.	.	.	.	.	.	.	.	180min	0.05mmol/kg	Tail flick method	"All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines."	"It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of &beta;-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that &beta;-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel &beta;-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury."
REF00553	PDC_02045	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	15 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02046	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	8 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02047	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	6 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02048	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	14 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02049	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	35 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02050	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	30 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01589	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	45 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02051	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	64 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02052	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	42 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01587	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	120 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01586	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	20 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01585	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	29 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01582	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	140 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01583	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	100 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01579	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	120 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01577	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	76 nM	nM	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02045	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup3</sup nM	<sup>3</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02046	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02047	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02048	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02049	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02050	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01589	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02051	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02052	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01587	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01586	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01585	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01582	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup5</sup nM	<sup>5</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01583	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01579	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01577	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	10<sup4</sup nM	<sup>4</sup> nM 	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02045	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	18 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02046	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	27 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02047	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	5 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02048	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	27 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02049	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	82 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02050	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	59 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01589	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	65 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02051	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	94 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02052	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	120 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01587	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	140 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01586	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	110 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01585	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	320 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01582	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	440 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01583	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	270 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01579	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	530 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01577	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	320 nM	nM	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02045	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02046	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02047	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02048	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	16 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02049	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02050	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01589	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02051	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	30 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02052	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	25 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01587	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01586	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01585	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01582	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01583	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	9 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01579	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01577	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02045	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02046	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02047	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02048	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02049	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02050	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01589	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02051	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02052	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01587	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01586	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01585	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01582	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01583	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01579	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01577	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02045	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02046	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02047	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02048	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	16 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02049	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02050	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01589	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02051	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	30 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_02052	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	25 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01587	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01586	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01585	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01582	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	84 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01583	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01579	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01577	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	5 days	.	.	"The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01576	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.89 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01575	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.87 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01574	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1.9 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01573	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.71 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01572	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.66 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01571	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1.1 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01570	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.07 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01569	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.44 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01576	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01575	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	40 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01574	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01573	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	86 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01572	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01571	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	77 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01570	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01569	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01576	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	56 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01575	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	46 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01574	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	53 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01573	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	121 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01572	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1500 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01571	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	70 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01570	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1400 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01569	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	230 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01576	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1.2 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01575	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.85 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01574	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	6.1 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01573	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1.9 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01572	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	2.3 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01571	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	2.4 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01570	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.51 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01569	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.78 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01576	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	40 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01575	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	18 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01574	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01573	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01572	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	10 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01571	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01570	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	50 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01569	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>+</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01576	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	40 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01575	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	50 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01574	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01573	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01572	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01571	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01570	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01569	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	HIV infection	HIV-1 LAI infected CEM/TK<sup>-</sup> cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01576	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	19 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01575	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	2 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01574	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01573	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01572	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01571	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01570	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	50 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01569	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal cytotoxicity concentration (CC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	MT4/HIV-1 cell	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01575	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	38.6 mM	mM	.	.	.	.	HIV Infection	Human immunodeficiency virus	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01573	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	110 mM	mM	.	.	.	.	HIV Infection	Human immunodeficiency virus	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00553	PDC_01571	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	105 mM	mM	.	.	.	.	HIV Infection	Human immunodeficiency virus	.	.	.	.	.	"Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 &mu;M and from 0.5 to 6.1 &mu;M were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 &mu;M (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 &mu;M in CEM-SS and 19 and 2 &mu;M in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity."	"We report on the synthesis of a series of peptideAZT (2A, 2B, 5A, 5B) and peptide-(AZT-MP) conjugates incorporating peptide sequences found in a nonapeptide known to be a HIV-PR substrate. We also selected the AZT-MP phosphoramidate peptide-conjugates containing an additional alanine residue directly linked to the phosphorus atom. Indeed, among the various aminoacid phosphoramidates of ddN analogues known so far, the alanine derivative was shown to be one of the most efficient ddN-MP delivery system. All these conjugates contain the scissile Phe-Pro motif. In the case of the AZT prodrugs, the AZT and peptide moieties were connected through an ester bond. To ensure a greater stability, particularly toward aminopeptidases, the N-terminal amino group of the peptide was masked by different protecting groups. In the case of the AZT-MP prodrugs, the various peptide moieties were connected via their N-terminal amino group to the AZT-phenoxy-phosphodiester group. We report also on (i) the stability of the peptide-AZT and peptide(AZT-MP) prodrugs when incubated in a physiological medium that does or does not contain 10% fetal calf serum, and in CEM cell lysates in order to mimic the behaviour of these compounds inside the cells, (ii) their ability to inhibit the HIV-PR activity and their susceptibility to be hydrolysed by PR, and (iii) their in vitro anti-HIV activities and cytotoxicities, which were evaluated in acutely-infected and uninfected MT4 and CEM cells, respectively. Moreover, their antiviral activities were also investigated in a thymidine kinase-deficient (TK- ) CEM cell line in order to gain further insight into their mechanism of action."
REF00602	PDC_02053	Colon carcinoma	Female C57BL/6 mice (6-8weeks) xenograft model.	Obtained from the Model Organism Data	High Expreesion	Tumor growth inhibition value (TGI)	98.00%	%	.	.	.	.	Mouse colon adenocarcinoma	MC-38 cell	.	.	12 days	0.5 mg/kg	.	"MC38 tumor-bearing mouse model was used to evaluate the antitumor activity of the integrated drug delivery system in vivo. After 2 weeks of treatment with saline, RT, R848, NIA-D1@R848, NIA-D1@R848+RT, and C16-D1@R848+RT, effects on inhibition of tumor growth and induction of antitumor immune response were investigated (Figure 6A). All groups inhibited the tumor growth in a certain extent compared with normal saline, while the combination group of NIA-D1@R848+RT had the strongest antitumor activity (Figure 6B,C). Although the C16-D1@R848+RT showed a better antitumor effect than NIA-D1@R848 or RT alone groups, the tumor inhibitory potency was slightly lower than NIA-D1@R848+RT group due to C16-D1@R848 not having a radio-sensitizing effect (Figure 6B,C)."	"In the present study, we designed a three-in-one nanoparticle that can simultaneously target the three obstacle stages of the CIC. We synthesized an amphiphilic peptide composed of hydrophobic RT sensitizer radio-sensitizer 2-(2-nitroimidazol-1-yl) acetic acid (NIA) and hydrophilic PD-L1 antagonist D1, by using a hydrophobic matrix metalloproteinase-2 (MMP-2) peptide substrate (PLGLAG) as the linker. The amphiphilic peptide NIA-LLPLGLAG-D1 (referred to as NIA-D1) could be co-assembled with hydrophobic TLR7/8 agonist R848 into nanoparticle NIA-D1@R848 (Figure 1A,B). When the nanoparticles circulated into the tumor stroma with high expression of MMP-2, they were cleaved by MMP-2, and the modified RT sensitizers NIA-LLPLG (referred to as NIA-PLG), LAG-D1 peptide, and R848 were released, respectively (Figure 1B). With the synergy of RT, NIA-PLG would improve the sensitivity of hypoxic cells to radiation, immune adjuvant R848 would promote the maturation of DCs, and D1 peptide would relieve the suppression of T cells (Figure 1B,C), which initiate a self-sustaining CIC."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	95.00%	%	.	.	.	.	Monocytic-macrophage leukemia	RAW264.7 cell	.	.	24 h	del	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	100.00%	%	.	.	.	.	Monocytic-macrophage leukemia	RAW264.7 cell	.	.	24 h	25&mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	100.00%	%	.	.	.	.	Monocytic-macrophage leukemia	RAW264.7 cell	.	.	24 h	50 &mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	90.00%	%	.	.	.	.	Monocytic-macrophage leukemia	RAW264.7 cell	.	.	24 h	100 &mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	80.00%	%	.	.	.	.	Monocytic-macrophage leukemia	RAW264.7 cell	.	.	24 h	200&mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	38.00%	%	.	.	.	.	Monocytic-macrophage leukemia	RAW264.7 cell	.	.	24 h	400 &mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	100.00%	%	.	.	.	.	Normal	NCTC clone 929 cell	.	.	24 h	del	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	97.00%	%	.	.	.	.	Normal	NCTC clone 929 cell	.	.	24 h	25&mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	85.00%	%	.	.	.	.	Normal	NCTC clone 929 cell	.	.	24 h	50 &mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	90.00%	%	.	.	.	.	Normal	NCTC clone 929 cell	.	.	24 h	100 &mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	82.00%	%	.	.	.	.	Normal	NCTC clone 929 cell	.	.	24 h	200&mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	95.00%	%	.	.	.	.	Normal	NCTC clone 929 cell	.	.	24 h	400 &mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	100.00%	%	.	.	.	.	Normal	Human corneal epithelial cell	.	.	24 h	del	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	98.00%	%	.	.	.	.	Normal	Human corneal epithelial cell	.	.	24 h	25&mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	97.00%	%	.	.	.	.	Normal	Human corneal epithelial cell	.	.	24 h	50 &mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	90.00%	%	.	.	.	.	Normal	Human corneal epithelial cell	.	.	24 h	100 &mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	75.00%	%	.	.	.	.	Normal	Human corneal epithelial cell	.	.	24 h	200&mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00600	PDC_02054	Uveitis	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	42.00%	%	.	.	.	.	Normal	Human corneal epithelial cell	.	.	24 h	400 &mu;M	MTT assay	"We assessed the in vitro cytotoxicity of IBF-HYD-GFFpY against Raw 264.7 macrophages, L-929 cells and HCEC cells by MTT assay. Fig. 3A clearly shows that both of IBF and IBF-HYD-GFFpY caused little cytotoxicity against all cell lines at concentrations below 200 &mu;M. When the concentration of IBF-HYD-GFFpY was up to 400 &mu;M, the viabilities of HCEC cells and Raw 264.7 macrophages declined significantly, indicating that the proposed IBF-HYD-GFFpY conjugate might cause apparent cytotoxicities towards HCEC cells and Raw 264.7 macrophages at concentrations above 200 &mu;M."	"In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 &mu;M. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	190 &mu;M	&mu;M	.	.	.	.	Candida krusei infection	Candida krusei DSM 11226	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms. "
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida glabrata infection	Candida glabrata DSM 6128	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms. "
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	8 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	15 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans ATCC 10231	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B3	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	45 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	23 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu5	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	15 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 48	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	23 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 138	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	23 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 190	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	23 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 247	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	23 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 574	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	23 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 604	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida krusei infection	Candida krusei DSM 11226	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida glabrata infection	Candida glabrata DSM 6128	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	15 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans ATCC 10231	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B3	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu5	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 48	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 138	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 190	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 247	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 574	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 604	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	62 &mu;M	&mu;M	.	.	.	.	Candida glabrata infection	Candida glabrata DSM 6128	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	15 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans ATCC 10231	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B3	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu5	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 48	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 138	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 190	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 247	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 574	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 604	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	125 &mu;M	&mu;M	.	.	.	.	Candida krusei infection	Candida krusei DSM 11226	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	125 &mu;M	&mu;M	.	.	.	.	Candida glabrata infection	Candida glabrata DSM 6128	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	15 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans ATCC 10231	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B3	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu5	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 48	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 138	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 190	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 247	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 574	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 604	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida glabrata infection	Candida glabrata DSM 6128	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans ATCC 10231	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B3	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu5	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 48	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 138	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 190	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 247	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 604	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	62 &mu;M	&mu;M	.	.	.	.	Candida krusei infection	Candida krusei DSM 11226	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	62 &mu;M	&mu;M	.	.	.	.	Candida glabrata infection	Candida glabrata DSM 6128	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	8 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	15 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans ATCC 10231	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B3	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	45 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu5	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	45 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 48	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	45 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 138	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	45 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 190	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	45 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 247	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	45 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 574	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	45 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 604	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida krusei infection	Candida krusei DSM 11226	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida glabrata infection	Candida glabrata DSM 6128	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans ATCC 10231	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B3	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu5	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 48	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 138	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 190	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 247	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 574	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 604	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	125 &mu;M	&mu;M	.	.	.	.	Candida glabrata infection	Candida glabrata DSM 6128	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida krusei infection	Candida krusei DSM 11226	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	31 &mu;M	&mu;M	.	.	.	.	Candida glabrata infection	Candida glabrata DSM 6128	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans ATCC 10231	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B3	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	190 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu5	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 48	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	190 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 138	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	190 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 190	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	190 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 247	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	190 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 574	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	190 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 604	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida krusei infection	Candida krusei DSM 11226	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida glabrata infection	Candida glabrata DSM 6128	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans ATCC 10231	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B3	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu5	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 48	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	31 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 138	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 190	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 247	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 574	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	90 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 604	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida krusei infection	Candida krusei DSM 11226	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	31 &mu;M	&mu;M	.	.	.	.	Candida glabrata infection	Candida glabrata DSM 6128	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	23 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	45 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans ATCC 10231	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	45 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B3	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu5	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 48	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	23 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 138	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	90 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 190	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	45 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 247	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	45 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 574	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	45 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 604	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida krusei infection	Candida krusei DSM 11226	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida glabrata infection	Candida glabrata DSM 6128	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans ATCC 10231	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B3	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu5	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 48	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 138	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 190	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 247	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 574	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half minimum inhibitory concentration (MIC<sub>90</sub>)	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 604	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida krusei infection	Candida krusei DSM 11226	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida glabrata infection	Candida glabrata DSM 6128	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	62 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans SC5314	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	125 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans ATCC 10231	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B3	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans B4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu4	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans Gu5	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 48	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 138	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 190	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 247	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 574	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Minimum fungicidal concentration	250 &mu;M	&mu;M	.	.	.	.	Candida albicans	Candida albicans 604	.	.	24 h	.	"Antifungal activity of the tested compounds against yeast cells was determined in 96-well plates, with minor modifications (CLSI, 2008). Suspensions of the microorganisms were prepared by taking one loop of pure culture into sterile water and adjusting optical density to 0.1 at 660 nm wavelength and further 50-fold dilution in RPMI 1640 medium, resulting in cell concentration of approximately 2 10<sup>4</sup> CFU/m. Then, 100 &mu;L of cells were added to the wells of a 96-well microtiter plate that contained 16-500 &mu;M tested compounds and 16-500 &mu;M of FLC or 0.2-62 &mu;M AmB. The plates were incubated for 24 h at 37 &deg;C. Each test was performed in triplicate. The final concentration of DMSO was ensured to be around 1% in all experiments. The MIC90 was defined as the lowest concentration of drug showing no visible growth; MIC50 was defined as the concentration that yielded at least 50% growth inhibition when compared with the growth control well. For determination of minimum fungicidal concentrations (MFC), small aliquots of suspensions (around 10 &mu;L) from each well were transferred using the pipette to YPD agar plates without inhibitors and incubated for 24 h at 37 &deg;C. The MFC was defined as the lowest concentration of drug at which no growth of the colonies was observed."	"The inactivity of FLCpOH confirmed that the drug derivative, used during the synthesis of our target compounds, did not exert any antifungal activity. All compounds displayed poor activity against the C. glabrata strain tested. Another identified advantage of FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 is their higher fungicidal potential compared to fluconazole. The MFC values against C. albicans reference strains were the same or only twice higher compared to MIC90. The high fungicidal activity of both conjugates was also confirmed with the kill-time assay. However, at least a 4 x MFC concentration was necessary to obtain an evident killing effect after 24 h of treatment."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	12.00 &plusmn; 0.93 &mu;M	&mu;M	.	.	.	.	Normal	Hs27 cell	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% maximal inhibitory concentration (IC50)	28.81 &plusmn; 0.87 &mu;M	&mu;M	.	.	.	.	Normal	Hs27 cell	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	14.45 &plusmn; 1.13 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% maximal inhibitory concentration (IC50)	34.30 &plusmn; 1.00 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	13.07 &plusmn; 0.35 &mu;M	&mu;M	.	.	.	.	Normal	Hs27 cell	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% maximal inhibitory concentration (IC50)	29.78 &plusmn; 0.29 &mu;M	&mu;M	.	.	.	.	Normal	Hs27 cell	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	15.16 &plusmn; 1.26 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% maximal inhibitory concentration (IC50)	34.03 &plusmn; 1.90 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	Hs27 cell	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	Hs27 cell	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02057	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	Hs27 cell	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	Hs27 cell	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	75.58 &plusmn; 1.73 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02058	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	Hs27 cell	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	Hs27 cell	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02059	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	90% maximal inhibitory concentration (IC50)	100 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cells	.	.	24 h	.	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	4.75 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	2 h	1 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	4.73 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	4 h	1 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	4.66 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	6 h	1 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	4.7 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	24 h	1 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	4.69 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	2 h	2 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	3.85 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	4 h	2 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	2.86 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	6 h	2 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	5.36 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	24 h	2 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	4.32 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	2 h	4 MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	3.35 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	4 h	4 MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	2.86 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	6 h	4 MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02055	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	1.75 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	24 h	4 MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	4.09 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	2 h	1 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	4.18 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	4 h	1 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	4.12 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	6 h	1 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	4.16 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	24 h	1 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	4.66 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	2 h	2 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	3.76 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	4 h	2 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	2.95 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	6 h	2 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	5.01 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	24 h	2 x MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	4.66 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	2 h	4 MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	3.76 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	4 h	4 MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	1.02 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	6 h	4 MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00604	PDC_02056	<i>Candida spp</i> infection	.	Revealed Based on the Cell Line Data	.	Logarithmic survival	1.08 CFU/ml	CFU/ml	.	.	.	.	Candida albicans infection	Candida albicans SC5314	.	.	24 h	4 MFC	MTT assay	"The adverse drug effects associated with the use of antimicrobials can be a major concern especially with antifungal agents due to the eukaryotic nature of both the organism being targeted and the host. Therefore, it was important to test the toxicity of novel fluconazole-based conjugates. To examine and compare the cytotoxicity of FLC and its derivatives, the cytotoxicities of the compounds were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two mammalian cell lines: human foreskin fibroblast cell line (Hs27) and human umbilical venous endothelial primary cells (HUVEC). The results showed that the FLC appeared to be less cytotoxic than its conjugates (Table 3). Among conjugates, FLCpOH-TP10-NH2 and FLCpOH-TP10<sup>-7</sup>-NH2 appeared to be more cytotoxic. However, the IC90 value for the human cells after 72 h treatment was comparable to the MIC50 value after 24 h treatment for most strains of C. albicans (Table S2)."	"Herein we report the chemical synthesis and biological activity of conjugates of fluconazole with (i) cell-penetrating peptides (CPP), namely TP10-NH2 and TP10-7-NH2, or (ii) antimicrobial peptides (AMP), such as LFcinB(2-11)-NH2, LFcinB[Nle1,11]-NH2 and HLopt2-NH2. Both constituents of produced conjugates (FLC and peptides) display different modes of antifungal activity and affect different molecular targets within fungal cells. CPPs serving as carrier peptides and are considered the fundamental part of an extensively developed concept of a drug delivery system; TP-10 is one of the most promising peptides in this family. These peptides effectively penetrate cell membrane. In our recent paper. we showed that TP10-NH2 can be successfully applied to design conjugates with antimicrobial activity. Modified fragments of bovine lactoferrin (LFcin) and human lactoferrin (HLopt2) are members of the AMP family, peptides that constitute an important segment of the bodys natural immunity against microorganisms."
REF00603	PDC_00349	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1.58&plusmn;0.07 nM	nM	.	.	.	.	Ovarian clear cell adenocarcinoma	ES-2 cell	.	.	72 h	.	MTT assay	"For mice bearing endometrial tumor xenografts, a similar dosage regimen to that for ovarian tumor xenografts was used as described previously for both docetaxel and TH1902. The growth of AN3-CA tumors was inhibited by both dosages of TH1902, whereas only "	"TH1902 is a peptide-drug conjugate with a payload of two docetaxel molecules ester-linked to a peptide (TH19P01) designed to recognize SORT1. Studies in breast and ovarian cancer cell lines have shown that TH1902 exploited SORT1s ligand internalization functions and exerted potent antiproliferative and anti-migratory effects. Within the cell, the docetaxel molecules are released from the conjugate and can then affect polymerization of microtubules leading to aberrant mitosis and apoptosis. Intravenous administration of TH1902 to mice bearing xenografts of MDA-MB-231 breast cancer cells demonstrated a marked superiority of TH1902 over free docetaxel in preventing the growth and relapse of subcutaneous xenografts. In a previous study, SORT1 was reported to have a role in vasculogenic mimicry (VM), and TH1902 was shown to inhibit in vitro VM in these cells and in the ES-2 ovarian cancer cell line."
REF00603	PDC_00349	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Apotosis rate	47.00%	%	.	.	.	.	Ovarian clear cell adenocarcinoma	ES-2 cell	.	.	5 h	2 &mu;M	Annexin X/PI staining combined with flow cytometry	"The results show that TH1902 induces more efficiently apoptosis in both cell lines when compared to docetaxel especially in SKOV3 cells. Overall, this suggests that receptor-mediated events appear to account for the increased effects of TH1902 within such a short time frame. To confirm the implication of SORT1 in TH1902 internalization and apoptosis induction, SORT1 was transiently silenced in ES-2 and SKOV3 cells. "	"TH1902 is a peptide-drug conjugate with a payload of two docetaxel molecules ester-linked to a peptide (TH19P01) designed to recognize SORT1. Studies in breast and ovarian cancer cell lines have shown that TH1902 exploited SORT1s ligand internalization functions and exerted potent antiproliferative and anti-migratory effects. Within the cell, the docetaxel molecules are released from the conjugate and can then affect polymerization of microtubules leading to aberrant mitosis and apoptosis. Intravenous administration of TH1902 to mice bearing xenografts of MDA-MB-231 breast cancer cells demonstrated a marked superiority of TH1902 over free docetaxel in preventing the growth and relapse of subcutaneous xenografts. In a previous study, SORT1 was reported to have a role in vasculogenic mimicry (VM), and TH1902 was shown to inhibit in vitro VM in these cells and in the ES-2 ovarian cancer cell line."
REF00603	PDC_00349	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.55 &plusmn; 0.21 nM	nM	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	72 h	.	MTT assay	"Cells were thus exposed to various concentrations of TH1902 or docetaxel, and the effects on cell proliferation were measured using the MTT detection assay. It is apparent that both reagents exerted a cytotoxic effect with IC50 values of TH1902 comparable to that of docetaxel at low nM concentrations in the four cell lines tested. This supports the rationale that conjugated docetaxel can be released from TH1902 and exert its anti-proliferative effect inside the targeted cancer cells. Parallel experiment showed that cell proliferation was unaffected by the free peptide (TH19P01) at concentrations up to 1000 nM."	"TH1902 is a peptide-drug conjugate with a payload of two docetaxel molecules ester-linked to a peptide (TH19P01) designed to recognize SORT1. Studies in breast and ovarian cancer cell lines have shown that TH1902 exploited SORT1s ligand internalization functions and exerted potent antiproliferative and anti-migratory effects. Within the cell, the docetaxel molecules are released from the conjugate and can then affect polymerization of microtubules leading to aberrant mitosis and apoptosis. Intravenous administration of TH1902 to mice bearing xenografts of MDA-MB-231 breast cancer cells demonstrated a marked superiority of TH1902 over free docetaxel in preventing the growth and relapse of subcutaneous xenografts. In a previous study, SORT1 was reported to have a role in vasculogenic mimicry (VM), and TH1902 was shown to inhibit in vitro VM in these cells and in the ES-2 ovarian cancer cell line."
REF00603	PDC_00349	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Apotosis rate	45.00%	%	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	5 h	2 &mu;M	Annexin X/PI staining combined with flow cytometry	"The results show that TH1902 induces more efficiently apoptosis in both cell lines when compared to docetaxel especially in SKOV3 cells. Overall, this suggests that receptor-mediated events appear to account for the increased effects of TH1902 within such a short time frame. To confirm the implication of SORT1 in TH1902 internalization and apoptosis induction, SORT1 was transiently silenced in ES-2 and SKOV3 cells. "	"TH1902 is a peptide-drug conjugate with a payload of two docetaxel molecules ester-linked to a peptide (TH19P01) designed to recognize SORT1. Studies in breast and ovarian cancer cell lines have shown that TH1902 exploited SORT1s ligand internalization functions and exerted potent antiproliferative and anti-migratory effects. Within the cell, the docetaxel molecules are released from the conjugate and can then affect polymerization of microtubules leading to aberrant mitosis and apoptosis. Intravenous administration of TH1902 to mice bearing xenografts of MDA-MB-231 breast cancer cells demonstrated a marked superiority of TH1902 over free docetaxel in preventing the growth and relapse of subcutaneous xenografts. In a previous study, SORT1 was reported to have a role in vasculogenic mimicry (VM), and TH1902 was shown to inhibit in vitro VM in these cells and in the ES-2 ovarian cancer cell line."
REF00603	PDC_00349	Endometrial cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	3.99 &plusmn; 0.96 nM	nM	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	.	"Cells were thus exposed to various concentrations of TH1902 or docetaxel, and the effects on cell proliferation were measured using the MTT detection assay. It is apparent that both reagents exerted a cytotoxic effect with IC50 values of TH1902 comparable to that of docetaxel at low nM concentrations in the four cell lines tested. This supports the rationale that conjugated docetaxel can be released from TH1902 and exert its anti-proliferative effect inside the targeted cancer cells. Parallel experiment showed that cell proliferation was unaffected by the free peptide (TH19P01) at concentrations up to 1000 nM."	"TH1902 is a peptide-drug conjugate with a payload of two docetaxel molecules ester-linked to a peptide (TH19P01) designed to recognize SORT1. Studies in breast and ovarian cancer cell lines have shown that TH1902 exploited SORT1s ligand internalization functions and exerted potent antiproliferative and anti-migratory effects. Within the cell, the docetaxel molecules are released from the conjugate and can then affect polymerization of microtubules leading to aberrant mitosis and apoptosis. Intravenous administration of TH1902 to mice bearing xenografts of MDA-MB-231 breast cancer cells demonstrated a marked superiority of TH1902 over free docetaxel in preventing the growth and relapse of subcutaneous xenografts. In a previous study, SORT1 was reported to have a role in vasculogenic mimicry (VM), and TH1902 was shown to inhibit in vitro VM in these cells and in the ES-2 ovarian cancer cell line."
REF00603	PDC_00349	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.29 &plusmn; 0.24 nM	nM	.	.	.	.	Endometrial adenocarcinoma	AN3-CA cell	.	.	72 h	.	.	"Cells were thus exposed to various concentrations of TH1902 or docetaxel, and the effects on cell proliferation were measured using the MTT detection assay. It is apparent that both reagents exerted a cytotoxic effect with IC50 values of TH1902 comparable to that of docetaxel at low nM concentrations in the four cell lines tested. This supports the rationale that conjugated docetaxel can be released from TH1902 and exert its anti-proliferative effect inside the targeted cancer cells. Parallel experiment showed that cell proliferation was unaffected by the free peptide (TH19P01) at concentrations up to 1000 nM."	"TH1902 is a peptide-drug conjugate with a payload of two docetaxel molecules ester-linked to a peptide (TH19P01) designed to recognize SORT1. Studies in breast and ovarian cancer cell lines have shown that TH1902 exploited SORT1s ligand internalization functions and exerted potent antiproliferative and anti-migratory effects. Within the cell, the docetaxel molecules are released from the conjugate and can then affect polymerization of microtubules leading to aberrant mitosis and apoptosis. Intravenous administration of TH1902 to mice bearing xenografts of MDA-MB-231 breast cancer cells demonstrated a marked superiority of TH1902 over free docetaxel in preventing the growth and relapse of subcutaneous xenografts. In a previous study, SORT1 was reported to have a role in vasculogenic mimicry (VM), and TH1902 was shown to inhibit in vitro VM in these cells and in the ES-2 ovarian cancer cell line."
REF00603	PDC_00349	Ovarian cancer	Female CD-1 nude mice xenograft model.	Obtained from the Model Organism Data	High Expreesion	Tumor growth inhibition value (TGI)	45.00%	%	.	.	.	.	Ewing sarcoma	ES2 cell	.	.	28 days	8.75 mg/kg	.	"In the ES-2 study, mice treated with low and high doses of TH1902 significantly inhibited the growth of tumors by, respectively, 45% and 87%, whereas both docetaxel groups, at equivalent docetaxel content, produced little effect (Figure 6A and Table 1). Low doses of docetaxel and low and high doses of TH1902 were well-tolerated with slight weight gain, whereas three weekly cycles of treatments with high doses of docetaxel (the MTD for this agent in mice) produced a small weight loss when compared to initial mice weights"	"TH1902 is a peptide-drug conjugate with a payload of two docetaxel molecules ester-linked to a peptide (TH19P01) designed to recognize SORT1. Studies in breast and ovarian cancer cell lines have shown that TH1902 exploited SORT1s ligand internalization functions and exerted potent antiproliferative and anti-migratory effects. Within the cell, the docetaxel molecules are released from the conjugate and can then affect polymerization of microtubules leading to aberrant mitosis and apoptosis. Intravenous administration of TH1902 to mice bearing xenografts of MDA-MB-231 breast cancer cells demonstrated a marked superiority of TH1902 over free docetaxel in preventing the growth and relapse of subcutaneous xenografts. In a previous study, SORT1 was reported to have a role in vasculogenic mimicry (VM), and TH1902 was shown to inhibit in vitro VM in these cells and in the ES-2 ovarian cancer cell line."
REF00603	PDC_00349	Ovarian cancer	Female CD-1 nude mice xenograft model.	Obtained from the Model Organism Data	High Expreesion	Tumor growth inhibition value (TGI)	87.00%	%	.	.	.	.	Ewing sarcoma	ES2 cell	.	.	28 days	35 mg/kg	.	"In the ES-2 study, mice treated with low and high doses of TH1902 significantly inhibited the growth of tumors by, respectively, 45% and 87%, whereas both docetaxel groups, at equivalent docetaxel content, produced little effect (Figure 6A and Table 1). Low doses of docetaxel and low and high doses of TH1902 were well-tolerated with slight weight gain, whereas three weekly cycles of treatments with high doses of docetaxel (the MTD for this agent in mice) produced a small weight loss when compared to initial mice weights"	"TH1902 is a peptide-drug conjugate with a payload of two docetaxel molecules ester-linked to a peptide (TH19P01) designed to recognize SORT1. Studies in breast and ovarian cancer cell lines have shown that TH1902 exploited SORT1s ligand internalization functions and exerted potent antiproliferative and anti-migratory effects. Within the cell, the docetaxel molecules are released from the conjugate and can then affect polymerization of microtubules leading to aberrant mitosis and apoptosis. Intravenous administration of TH1902 to mice bearing xenografts of MDA-MB-231 breast cancer cells demonstrated a marked superiority of TH1902 over free docetaxel in preventing the growth and relapse of subcutaneous xenografts. In a previous study, SORT1 was reported to have a role in vasculogenic mimicry (VM), and TH1902 was shown to inhibit in vitro VM in these cells and in the ES-2 ovarian cancer cell line."
REF00603	PDC_00349	Ovarian cancer	Female CD-1 nude mice xenograft model.	Obtained from the Model Organism Data	High Expreesion	Tumor growth inhibition value (TGI)	69.00%	%	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	28 days	8.75 mg/kg	.	"In the SKOV3 study, mice treated with low and high doses of TH1902 showed significant inhibitions of tumor growth where only high dose of docetaxel produced this effect (Figure 6B). When compared to vehicle endpoint (Day 28), low dose of TH1902 produced similar tumor growth inhibitions when compared to high dose of docetaxel (69% vs. 84%, respectively) while high dose of TH1902 induced stronger inhibition with slight regression of tumors (Table 1). Moreover, mice treated with high dose of TH1902 showed prolonged inhibitory effect (up to Day 46) where docetaxel-treated mice could not sustain this effect, which is marked by tumor regrowth (Figure 6B). "	"TH1902 is a peptide-drug conjugate with a payload of two docetaxel molecules ester-linked to a peptide (TH19P01) designed to recognize SORT1. Studies in breast and ovarian cancer cell lines have shown that TH1902 exploited SORT1s ligand internalization functions and exerted potent antiproliferative and anti-migratory effects. Within the cell, the docetaxel molecules are released from the conjugate and can then affect polymerization of microtubules leading to aberrant mitosis and apoptosis. Intravenous administration of TH1902 to mice bearing xenografts of MDA-MB-231 breast cancer cells demonstrated a marked superiority of TH1902 over free docetaxel in preventing the growth and relapse of subcutaneous xenografts. In a previous study, SORT1 was reported to have a role in vasculogenic mimicry (VM), and TH1902 was shown to inhibit in vitro VM in these cells and in the ES-2 ovarian cancer cell line."
REF00603	PDC_00349	Ovarian cancer	Female CD-1 nude mice xenograft model.	Obtained from the Model Organism Data	High Expreesion	Tumor growth inhibition value (TGI)	84.00%	%	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	28 days	35 mg/kg	.	"In the SKOV3 study, mice treated with low and high doses of TH1902 showed significant inhibitions of tumor growth where only high dose of docetaxel produced this effect (Figure 6B). When compared to vehicle endpoint (Day 28), low dose of TH1902 produced similar tumor growth inhibitions when compared to high dose of docetaxel (69% vs. 84%, respectively) while high dose of TH1902 induced stronger inhibition with slight regression of tumors (Table 1). Moreover, mice treated with high dose of TH1902 showed prolonged inhibitory effect (up to Day 46) where docetaxel-treated mice could not sustain this effect, which is marked by tumor regrowth (Figure 6B). "	"TH1902 is a peptide-drug conjugate with a payload of two docetaxel molecules ester-linked to a peptide (TH19P01) designed to recognize SORT1. Studies in breast and ovarian cancer cell lines have shown that TH1902 exploited SORT1s ligand internalization functions and exerted potent antiproliferative and anti-migratory effects. Within the cell, the docetaxel molecules are released from the conjugate and can then affect polymerization of microtubules leading to aberrant mitosis and apoptosis. Intravenous administration of TH1902 to mice bearing xenografts of MDA-MB-231 breast cancer cells demonstrated a marked superiority of TH1902 over free docetaxel in preventing the growth and relapse of subcutaneous xenografts. In a previous study, SORT1 was reported to have a role in vasculogenic mimicry (VM), and TH1902 was shown to inhibit in vitro VM in these cells and in the ES-2 ovarian cancer cell line."
REF00603	PDC_00349	Endometrial cancer	Female CD-1 nude mice xenograft model.	Obtained from the Model Organism Data	High Expreesion	Tumor growth inhibition value (TGI)	74.00%	%	.	.	.	.	Endometrial adenocarcinoma	AN3-CA cell	.	.	28 days	8.75 mg/kg	.	"For mice bearing endometrial tumor xenografts, a similar dosage regimen to that for ovarian tumor xenografts was used as described previously for both docetaxel and TH1902. The growth of AN3-CA tumors was inhibited by both dosages of TH1902, whereas only a high dose of docetaxel could produce this effect. When compared to vehicle endpoint, low dose of TH1902 significantly inhibited the growth of AN3-CA tumors by 74%, whereas both high doses of docetaxel and TH1902 induced tumor regressions. Interestingly, a large portion of tumors (5 out of 6) within the high-dose TH1902 group were unmeasurable or remained in regression for a prolonged period (up to Day 54), whereas tumors in the equivalent docetaxel dose were unresponsive and regrew before the end of treatments. The two high doses were diminished by half for the final two treatments due to weight loss in the animals receiving high-dose docetaxel. Rapid weight loss was associated with administration of high dosage docetaxel, but this was reversed when the dosage was halved. In contrast, only mild weight loss was observed in animals administered with high-dosage TH1902."	"TH1902 is a peptide-drug conjugate with a payload of two docetaxel molecules ester-linked to a peptide (TH19P01) designed to recognize SORT1. Studies in breast and ovarian cancer cell lines have shown that TH1902 exploited SORT1s ligand internalization functions and exerted potent antiproliferative and anti-migratory effects. Within the cell, the docetaxel molecules are released from the conjugate and can then affect polymerization of microtubules leading to aberrant mitosis and apoptosis. Intravenous administration of TH1902 to mice bearing xenografts of MDA-MB-231 breast cancer cells demonstrated a marked superiority of TH1902 over free docetaxel in preventing the growth and relapse of subcutaneous xenografts. In a previous study, SORT1 was reported to have a role in vasculogenic mimicry (VM), and TH1902 was shown to inhibit in vitro VM in these cells and in the ES-2 ovarian cancer cell line."
REF00603	PDC_00349	Endometrial cancer	Female CD-1 nude mice xenograft model.	Obtained from the Model Organism Data	High Expreesion	Tumor growth inhibition value (TGI)	100.00%	%	.	.	.	.	Endometrial adenocarcinoma	AN3-CA cell	.	.	28 days	35 mg/kg	.	"For mice bearing endometrial tumor xenografts, a similar dosage regimen to that for ovarian tumor xenografts was used as described previously for both docetaxel and TH1902. The growth of AN3-CA tumors was inhibited by both dosages of TH1902, whereas only a high dose of docetaxel could produce this effect. When compared to vehicle endpoint, low dose of TH1902 significantly inhibited the growth of AN3-CA tumors by 74%, whereas both high doses of docetaxel and TH1902 induced tumor regressions. Interestingly, a large portion of tumors (5 out of 6) within the high-dose TH1902 group were unmeasurable or remained in regression for a prolonged period (up to Day 54), whereas tumors in the equivalent docetaxel dose were unresponsive and regrew before the end of treatments. The two high doses were diminished by half for the final two treatments due to weight loss in the animals receiving high-dose docetaxel. Rapid weight loss was associated with administration of high dosage docetaxel, but this was reversed when the dosage was halved. In contrast, only mild weight loss was observed in animals administered with high-dosage TH1902."	"TH1902 is a peptide-drug conjugate with a payload of two docetaxel molecules ester-linked to a peptide (TH19P01) designed to recognize SORT1. Studies in breast and ovarian cancer cell lines have shown that TH1902 exploited SORT1s ligand internalization functions and exerted potent antiproliferative and anti-migratory effects. Within the cell, the docetaxel molecules are released from the conjugate and can then affect polymerization of microtubules leading to aberrant mitosis and apoptosis. Intravenous administration of TH1902 to mice bearing xenografts of MDA-MB-231 breast cancer cells demonstrated a marked superiority of TH1902 over free docetaxel in preventing the growth and relapse of subcutaneous xenografts. In a previous study, SORT1 was reported to have a role in vasculogenic mimicry (VM), and TH1902 was shown to inhibit in vitro VM in these cells and in the ES-2 ovarian cancer cell line."
REF00601	PDC_02060	Osteoporosis	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	4.38&mu;M	&mu;M	.	.	.	.	Monocytic-macrophage leukemia	RAW264.7 cell	.	.	3 days	.	Tartrate-resistant acid phosphatase staining	"The next move was to evaluate their biological activity against RANKL-induced osteoclast differentiation on RAW264.7 cells via tartrate-resistant acid phosphatase (TRAP) staining (Fig. 3 and ESI Fig. S6). Different concentrations of PDCs and M19 were co-cultured with RANKL and colony stimulating factor 1 (CSF-1) in RAW264.7 cells. After 3 days' treatment, both compounds exhibited dose-dependently inhibitory effects on the TRAP activity and the IC50 was 2.41 &mu;M (M19), 4.38 &mu;M (BTM19-1), 2.62 &mu;M (BTM19-2) and 2.84 &mu;M (BTM19-3). These results indicated that, with the exception of BTM19-1, the osteoclast suppression effect produced by the M19-based PDCs was equivalent to that of the free M19, confirming the bone-targeted PDC modification strategy did not significantly affect the activity of the prototype drug. However, BTM19-1 exhibited a heavily decreased activity. A reasonable speculation might be that the steric hindrance caused by its shorter PEG linker prevented cathepsin K from substrates cleaving, which delayed the release of the prototype drug."	"M19 was developed and represented the new generation of highly active matrine derivative because of its great inhibitory effect on pro-inflammatory cytokine TNF-a and NF-kB transcriptional activity, making it a promising anti-inflammatory drug candidate.9 Recently, we showed that M19 could block NF-kB, AKt, MAPK and other signalling pathways by stabilizing ribosomal protein S5 (RPS5), thereby inhibiting RANKL-induced osteoclast differentiation and alleviating bone loss in ovariectomized mice. M19-based bone targeting PDCs were rationally developed by coupling M19 with bone targeting peptide and cathepsin K sensitive smart linker through suitable spacers. These PDCs showed excellent specificity for hydroxyapatite (HA), the composition of bone tissue and tooth, and inhibitory activity on osteoclast differentiation, providing a valuable example for overcoming the shortcomings of natural product source compounds and improve their druggability."
REF00601	PDC_02061	Osteoporosis	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	2.62 &mu;M	&mu;M	.	.	.	.	Monocytic-macrophage leukemia	RAW264.7 cell	.	.	3 days	.	Tartrate-resistant acid phosphatase staining	"The next move was to evaluate their biological activity against RANKL-induced osteoclast differentiation on RAW264.7 cells via tartrate-resistant acid phosphatase (TRAP) staining (Fig. 3 and ESI Fig. S6). Different concentrations of PDCs and M19 were co-cultured with RANKL and colony stimulating factor 1 (CSF-1) in RAW264.7 cells. After 3 days' treatment, both compounds exhibited dose-dependently inhibitory effects on the TRAP activity and the IC50 was 2.41 &mu;M (M19), 4.38 &mu;M (BTM19-1), 2.62 &mu;M (BTM19-2) and 2.84 &mu;M (BTM19-3). These results indicated that, with the exception of BTM19-1, the osteoclast suppression effect produced by the M19-based PDCs was equivalent to that of the free M19, confirming the bone-targeted PDC modification strategy did not significantly affect the activity of the prototype drug. However, BTM19-1 exhibited a heavily decreased activity. A reasonable speculation might be that the steric hindrance caused by its shorter PEG linker prevented cathepsin K from substrates cleaving, which delayed the release of the prototype drug."	"M19 was developed and represented the new generation of highly active matrine derivative because of its great inhibitory effect on pro-inflammatory cytokine TNF-a and NF-kB transcriptional activity, making it a promising anti-inflammatory drug candidate.9 Recently, we showed that M19 could block NF-kB, AKt, MAPK and other signalling pathways by stabilizing ribosomal protein S5 (RPS5), thereby inhibiting RANKL-induced osteoclast differentiation and alleviating bone loss in ovariectomized mice. M19-based bone targeting PDCs were rationally developed by coupling M19 with bone targeting peptide and cathepsin K sensitive smart linker through suitable spacers. These PDCs showed excellent specificity for hydroxyapatite (HA), the composition of bone tissue and tooth, and inhibitory activity on osteoclast differentiation, providing a valuable example for overcoming the shortcomings of natural product source compounds and improve their druggability."
REF00601	PDC_02062	Osteoporosis	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	2.84 &mu;M	&mu;M	.	.	.	.	Monocytic-macrophage leukemia	RAW264.7 cell	.	.	3 days	.	Tartrate-resistant acid phosphatase staining	"The next move was to evaluate their biological activity against RANKL-induced osteoclast differentiation on RAW264.7 cells via tartrate-resistant acid phosphatase (TRAP) staining (Fig. 3 and ESI Fig. S6). Different concentrations of PDCs and M19 were co-cultured with RANKL and colony stimulating factor 1 (CSF-1) in RAW264.7 cells. After 3 days' treatment, both compounds exhibited dose-dependently inhibitory effects on the TRAP activity and the IC50 was 2.41 &mu;M (M19), 4.38 &mu;M (BTM19-1), 2.62 &mu;M (BTM19-2) and 2.84 &mu;M (BTM19-3). These results indicated that, with the exception of BTM19-1, the osteoclast suppression effect produced by the M19-based PDCs was equivalent to that of the free M19, confirming the bone-targeted PDC modification strategy did not significantly affect the activity of the prototype drug. However, BTM19-1 exhibited a heavily decreased activity. A reasonable speculation might be that the steric hindrance caused by its shorter PEG linker prevented cathepsin K from substrates cleaving, which delayed the release of the prototype drug."	"M19 was developed and represented the new generation of highly active matrine derivative because of its great inhibitory effect on pro-inflammatory cytokine TNF-a and NF-kB transcriptional activity, making it a promising anti-inflammatory drug candidate.9 Recently, we showed that M19 could block NF-kB, AKt, MAPK and other signalling pathways by stabilizing ribosomal protein S5 (RPS5), thereby inhibiting RANKL-induced osteoclast differentiation and alleviating bone loss in ovariectomized mice. M19-based bone targeting PDCs were rationally developed by coupling M19 with bone targeting peptide and cathepsin K sensitive smart linker through suitable spacers. These PDCs showed excellent specificity for hydroxyapatite (HA), the composition of bone tissue and tooth, and inhibitory activity on osteoclast differentiation, providing a valuable example for overcoming the shortcomings of natural product source compounds and improve their druggability."
REF00587	PDC_02063	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	139.541 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U-87MG cell	.	.	4 h	.	MTS assay	"However, in the MMP2 siRNAtransfected U87MG and U251, SynB3PVGLIGPTX could result in an extremely lower inhibitory effect on cell proliferation than that treated at the same concentration ranges (25 x 10<sup>-6</sup>, 50 x 10<sup>-6</sup>, 75 x 10<sup>-6</sup>, and 100 x 10<sup>-6</sup> M) in the U87MG and U251 cell lines (Figure 5G,,H).H). The absence of MMP2 manifested as an obviously reducing trend of IC50 of SynB3PVGLIGPTX in both cell lines (Table 3). These results indicated that SynB3PVGLIGPTX could only inhibit cell proliferation based on the presence of MMP2, which suggested that SynB3PVGLIGPTX performs a specific inhibitory action on the proliferation of GBM cells. In addition, in order to further verify the mechanism underlying the specific inhibitory activity of SynB3PVGLIGPTX on GBM cell proliferation, a supplementary experiment was performed using SynB3PTXtreated cells as inactive control groups. The results showed that the inhibition rates of SynB3PTX without an MMP2sensitive linker (PVGLIG) in U87MG and U251 were extremely low, at a nearzero level. Based on these observations, we confirmed that SynB3PVGLIGPTX has a specific antigrowth activity, that is, only in the presence of MMP2, the sensitive linker (PVGLIG) contained in SynB3PVGLIGPTX can be specifically hydrolyzed to release PTX, thereby inhibiting the proliferation of GBM cells."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	45.787 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U-87MG cell	.	.	24 h	.	MTS assay	"However, in the MMP2 siRNAtransfected U87MG and U251, SynB3PVGLIGPTX could result in an extremely lower inhibitory effect on cell proliferation than that treated at the same concentration ranges (25 x 10<sup>-6</sup>, 50 x 10<sup>-6</sup>, 75 x 10<sup>-6</sup>, and 100 x 10<sup>-6</sup> M) in the U87MG and U251 cell lines (Figure 5G,,H).H). The absence of MMP2 manifested as an obviously reducing trend of IC50 of SynB3PVGLIGPTX in both cell lines (Table 3). These results indicated that SynB3PVGLIGPTX could only inhibit cell proliferation based on the presence of MMP2, which suggested that SynB3PVGLIGPTX performs a specific inhibitory action on the proliferation of GBM cells. In addition, in order to further verify the mechanism underlying the specific inhibitory activity of SynB3PVGLIGPTX on GBM cell proliferation, a supplementary experiment was performed using SynB3PTXtreated cells as inactive control groups. The results showed that the inhibition rates of SynB3PTX without an MMP2sensitive linker (PVGLIG) in U87MG and U251 were extremely low, at a nearzero level. Based on these observations, we confirmed that SynB3PVGLIGPTX has a specific antigrowth activity, that is, only in the presence of MMP2, the sensitive linker (PVGLIG) contained in SynB3PVGLIGPTX can be specifically hydrolyzed to release PTX, thereby inhibiting the proliferation of GBM cells."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	31.981 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U-87MG cell	.	.	48 h	.	MTS assay	"However, in the MMP2 siRNAtransfected U87MG and U251, SynB3PVGLIGPTX could result in an extremely lower inhibitory effect on cell proliferation than that treated at the same concentration ranges (25 x 10<sup>-6</sup>, 50 x 10<sup>-6</sup>, 75 x 10<sup>-6</sup>, and 100 x 10<sup>-6</sup> M) in the U87MG and U251 cell lines (Figure 5G,,H).H). The absence of MMP2 manifested as an obviously reducing trend of IC50 of SynB3PVGLIGPTX in both cell lines (Table 3). These results indicated that SynB3PVGLIGPTX could only inhibit cell proliferation based on the presence of MMP2, which suggested that SynB3PVGLIGPTX performs a specific inhibitory action on the proliferation of GBM cells. In addition, in order to further verify the mechanism underlying the specific inhibitory activity of SynB3PVGLIGPTX on GBM cell proliferation, a supplementary experiment was performed using SynB3PTXtreated cells as inactive control groups. The results showed that the inhibition rates of SynB3PTX without an MMP2sensitive linker (PVGLIG) in U87MG and U251 were extremely low, at a nearzero level. Based on these observations, we confirmed that SynB3PVGLIGPTX has a specific antigrowth activity, that is, only in the presence of MMP2, the sensitive linker (PVGLIG) contained in SynB3PVGLIGPTX can be specifically hydrolyzed to release PTX, thereby inhibiting the proliferation of GBM cells."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	311.219 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U-87MG cell	.	.	4 h	.	MTS assay	"However, in the MMP2 siRNAtransfected U87MG and U251, SynB3PVGLIGPTX could result in an extremely lower inhibitory effect on cell proliferation than that treated at the same concentration ranges (25 x 10<sup>-6</sup>, 50 x 10<sup>-6</sup>, 75 x 10<sup>-6</sup>, and 100 x 10<sup>-6</sup> M) in the U87MG and U251 cell lines (Figure 5G,,H).H). The absence of MMP2 manifested as an obviously reducing trend of IC50 of SynB3PVGLIGPTX in both cell lines (Table 3). These results indicated that SynB3PVGLIGPTX could only inhibit cell proliferation based on the presence of MMP2, which suggested that SynB3PVGLIGPTX performs a specific inhibitory action on the proliferation of GBM cells. In addition, in order to further verify the mechanism underlying the specific inhibitory activity of SynB3PVGLIGPTX on GBM cell proliferation, a supplementary experiment was performed using SynB3PTXtreated cells as inactive control groups. The results showed that the inhibition rates of SynB3PTX without an MMP2sensitive linker (PVGLIG) in U87MG and U251 were extremely low, at a nearzero level. Based on these observations, we confirmed that SynB3PVGLIGPTX has a specific antigrowth activity, that is, only in the presence of MMP2, the sensitive linker (PVGLIG) contained in SynB3PVGLIGPTX can be specifically hydrolyzed to release PTX, thereby inhibiting the proliferation of GBM cells."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	219.364 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U-87MG cell	.	.	24 h	.	MTS assay	"However, in the MMP2 siRNAtransfected U87MG and U251, SynB3PVGLIGPTX could result in an extremely lower inhibitory effect on cell proliferation than that treated at the same concentration ranges (25 x 10<sup>-6</sup>, 50 x 10<sup>-6</sup>, 75 x 10<sup>-6</sup>, and 100 x 10<sup>-6</sup> M) in the U87MG and U251 cell lines (Figure 5G,,H).H). The absence of MMP2 manifested as an obviously reducing trend of IC50 of SynB3PVGLIGPTX in both cell lines (Table 3). These results indicated that SynB3PVGLIGPTX could only inhibit cell proliferation based on the presence of MMP2, which suggested that SynB3PVGLIGPTX performs a specific inhibitory action on the proliferation of GBM cells. In addition, in order to further verify the mechanism underlying the specific inhibitory activity of SynB3PVGLIGPTX on GBM cell proliferation, a supplementary experiment was performed using SynB3PTXtreated cells as inactive control groups. The results showed that the inhibition rates of SynB3PTX without an MMP2sensitive linker (PVGLIG) in U87MG and U251 were extremely low, at a nearzero level. Based on these observations, we confirmed that SynB3PVGLIGPTX has a specific antigrowth activity, that is, only in the presence of MMP2, the sensitive linker (PVGLIG) contained in SynB3PVGLIGPTX can be specifically hydrolyzed to release PTX, thereby inhibiting the proliferation of GBM cells."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	172.180 &mu;M	&mu;M	.	.	.	.	Glioblastoma	U-87MG cell	.	.	48 h	.	MTS assay	"However, in the MMP2 siRNAtransfected U87MG and U251, SynB3PVGLIGPTX could result in an extremely lower inhibitory effect on cell proliferation than that treated at the same concentration ranges (25 x 10<sup>-6</sup>, 50 x 10<sup>-6</sup>, 75 x 10<sup>-6</sup>, and 100 x 10<sup>-6</sup> M) in the U87MG and U251 cell lines (Figure 5G,,H).H). The absence of MMP2 manifested as an obviously reducing trend of IC50 of SynB3PVGLIGPTX in both cell lines (Table 3). These results indicated that SynB3PVGLIGPTX could only inhibit cell proliferation based on the presence of MMP2, which suggested that SynB3PVGLIGPTX performs a specific inhibitory action on the proliferation of GBM cells. In addition, in order to further verify the mechanism underlying the specific inhibitory activity of SynB3PVGLIGPTX on GBM cell proliferation, a supplementary experiment was performed using SynB3PTXtreated cells as inactive control groups. The results showed that the inhibition rates of SynB3PTX without an MMP2sensitive linker (PVGLIG) in U87MG and U251 were extremely low, at a nearzero level. Based on these observations, we confirmed that SynB3PVGLIGPTX has a specific antigrowth activity, that is, only in the presence of MMP2, the sensitive linker (PVGLIG) contained in SynB3PVGLIGPTX can be specifically hydrolyzed to release PTX, thereby inhibiting the proliferation of GBM cells."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	115.846 &mu;M	&mu;M	.	.	.	.	Astrocytoma	U-251MG cell	.	.	4 h	.	MTS assay	"However, in the MMP2 siRNAtransfected U87MG and U251, SynB3PVGLIGPTX could result in an extremely lower inhibitory effect on cell proliferation than that treated at the same concentration ranges (25 x 10<sup>-6</sup>, 50 x 10<sup>-6</sup>, 75 x 10<sup>-6</sup>, and 100 x 10<sup>-6</sup> M) in the U87MG and U251 cell lines (Figure 5G,,H).H). The absence of MMP2 manifested as an obviously reducing trend of IC50 of SynB3PVGLIGPTX in both cell lines (Table 3). These results indicated that SynB3PVGLIGPTX could only inhibit cell proliferation based on the presence of MMP2, which suggested that SynB3PVGLIGPTX performs a specific inhibitory action on the proliferation of GBM cells. In addition, in order to further verify the mechanism underlying the specific inhibitory activity of SynB3PVGLIGPTX on GBM cell proliferation, a supplementary experiment was performed using SynB3PTXtreated cells as inactive control groups. The results showed that the inhibition rates of SynB3PTX without an MMP2sensitive linker (PVGLIG) in U87MG and U251 were extremely low, at a nearzero level. Based on these observations, we confirmed that SynB3PVGLIGPTX has a specific antigrowth activity, that is, only in the presence of MMP2, the sensitive linker (PVGLIG) contained in SynB3PVGLIGPTX can be specifically hydrolyzed to release PTX, thereby inhibiting the proliferation of GBM cells."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	41.413 &mu;M	&mu;M	.	.	.	.	Astrocytoma	U-251MG cell	.	.	24 h	.	MTS assay	"However, in the MMP2 siRNAtransfected U87MG and U251, SynB3PVGLIGPTX could result in an extremely lower inhibitory effect on cell proliferation than that treated at the same concentration ranges (25 x 10<sup>-6</sup>, 50 x 10<sup>-6</sup>, 75 x 10<sup>-6</sup>, and 100 x 10<sup>-6</sup> M) in the U87MG and U251 cell lines (Figure 5G,,H).H). The absence of MMP2 manifested as an obviously reducing trend of IC50 of SynB3PVGLIGPTX in both cell lines (Table 3). These results indicated that SynB3PVGLIGPTX could only inhibit cell proliferation based on the presence of MMP2, which suggested that SynB3PVGLIGPTX performs a specific inhibitory action on the proliferation of GBM cells. In addition, in order to further verify the mechanism underlying the specific inhibitory activity of SynB3PVGLIGPTX on GBM cell proliferation, a supplementary experiment was performed using SynB3PTXtreated cells as inactive control groups. The results showed that the inhibition rates of SynB3PTX without an MMP2sensitive linker (PVGLIG) in U87MG and U251 were extremely low, at a nearzero level. Based on these observations, we confirmed that SynB3PVGLIGPTX has a specific antigrowth activity, that is, only in the presence of MMP2, the sensitive linker (PVGLIG) contained in SynB3PVGLIGPTX can be specifically hydrolyzed to release PTX, thereby inhibiting the proliferation of GBM cells."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	27.366 &mu;M	&mu;M	.	.	.	.	Astrocytoma	U-251MG cell	.	.	48 h	.	MTS assay	"However, in the MMP2 siRNAtransfected U87MG and U251, SynB3PVGLIGPTX could result in an extremely lower inhibitory effect on cell proliferation than that treated at the same concentration ranges (25 x 10<sup>-6</sup>, 50 x 10<sup>-6</sup>, 75 x 10<sup>-6</sup>, and 100 x 10<sup>-6</sup> M) in the U87MG and U251 cell lines (Figure 5G,,H).H). The absence of MMP2 manifested as an obviously reducing trend of IC50 of SynB3PVGLIGPTX in both cell lines (Table 3). These results indicated that SynB3PVGLIGPTX could only inhibit cell proliferation based on the presence of MMP2, which suggested that SynB3PVGLIGPTX performs a specific inhibitory action on the proliferation of GBM cells. In addition, in order to further verify the mechanism underlying the specific inhibitory activity of SynB3PVGLIGPTX on GBM cell proliferation, a supplementary experiment was performed using SynB3PTXtreated cells as inactive control groups. The results showed that the inhibition rates of SynB3PTX without an MMP2sensitive linker (PVGLIG) in U87MG and U251 were extremely low, at a nearzero level. Based on these observations, we confirmed that SynB3PVGLIGPTX has a specific antigrowth activity, that is, only in the presence of MMP2, the sensitive linker (PVGLIG) contained in SynB3PVGLIGPTX can be specifically hydrolyzed to release PTX, thereby inhibiting the proliferation of GBM cells."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	165.602 &mu;M	&mu;M	.	.	.	.	Astrocytoma	U-251MG cell	.	.	4 h	.	MTS assay	"However, in the MMP2 siRNAtransfected U87MG and U251, SynB3PVGLIGPTX could result in an extremely lower inhibitory effect on cell proliferation than that treated at the same concentration ranges (25 x 10<sup>-6</sup>, 50 x 10<sup>-6</sup>, 75 x 10<sup>-6</sup>, and 100 x 10<sup>-6</sup> M) in the U87MG and U251 cell lines (Figure 5G,,H).H). The absence of MMP2 manifested as an obviously reducing trend of IC50 of SynB3PVGLIGPTX in both cell lines (Table 3). These results indicated that SynB3PVGLIGPTX could only inhibit cell proliferation based on the presence of MMP2, which suggested that SynB3PVGLIGPTX performs a specific inhibitory action on the proliferation of GBM cells. In addition, in order to further verify the mechanism underlying the specific inhibitory activity of SynB3PVGLIGPTX on GBM cell proliferation, a supplementary experiment was performed using SynB3PTXtreated cells as inactive control groups. The results showed that the inhibition rates of SynB3PTX without an MMP2sensitive linker (PVGLIG) in U87MG and U251 were extremely low, at a nearzero level. Based on these observations, we confirmed that SynB3PVGLIGPTX has a specific antigrowth activity, that is, only in the presence of MMP2, the sensitive linker (PVGLIG) contained in SynB3PVGLIGPTX can be specifically hydrolyzed to release PTX, thereby inhibiting the proliferation of GBM cells."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	207.674 &mu;M	&mu;M	.	.	.	.	Astrocytoma	U-251MG cell	.	.	24 h	.	MTS assay	"However, in the MMP2 siRNAtransfected U87MG and U251, SynB3PVGLIGPTX could result in an extremely lower inhibitory effect on cell proliferation than that treated at the same concentration ranges (25 x 10<sup>-6</sup>, 50 x 10<sup>-6</sup>, 75 x 10<sup>-6</sup>, and 100 x 10<sup>-6</sup> M) in the U87MG and U251 cell lines (Figure 5G,,H).H). The absence of MMP2 manifested as an obviously reducing trend of IC50 of SynB3PVGLIGPTX in both cell lines (Table 3). These results indicated that SynB3PVGLIGPTX could only inhibit cell proliferation based on the presence of MMP2, which suggested that SynB3PVGLIGPTX performs a specific inhibitory action on the proliferation of GBM cells. In addition, in order to further verify the mechanism underlying the specific inhibitory activity of SynB3PVGLIGPTX on GBM cell proliferation, a supplementary experiment was performed using SynB3PTXtreated cells as inactive control groups. The results showed that the inhibition rates of SynB3PTX without an MMP2sensitive linker (PVGLIG) in U87MG and U251 were extremely low, at a nearzero level. Based on these observations, we confirmed that SynB3PVGLIGPTX has a specific antigrowth activity, that is, only in the presence of MMP2, the sensitive linker (PVGLIG) contained in SynB3PVGLIGPTX can be specifically hydrolyzed to release PTX, thereby inhibiting the proliferation of GBM cells."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	176.806 &mu;M	&mu;M	.	.	.	.	Astrocytoma	U-251MG cell	.	.	48 h	.	MTS assay	"However, in the MMP2 siRNAtransfected U87MG and U251, SynB3PVGLIGPTX could result in an extremely lower inhibitory effect on cell proliferation than that treated at the same concentration ranges (25 x 10<sup>-6</sup>, 50 x 10<sup>-6</sup>, 75 x 10<sup>-6</sup>, and 100 x 10<sup>-6</sup> M) in the U87MG and U251 cell lines (Figure 5G,,H).H). The absence of MMP2 manifested as an obviously reducing trend of IC50 of SynB3PVGLIGPTX in both cell lines (Table 3). These results indicated that SynB3PVGLIGPTX could only inhibit cell proliferation based on the presence of MMP2, which suggested that SynB3PVGLIGPTX performs a specific inhibitory action on the proliferation of GBM cells. In addition, in order to further verify the mechanism underlying the specific inhibitory activity of SynB3PVGLIGPTX on GBM cell proliferation, a supplementary experiment was performed using SynB3PTXtreated cells as inactive control groups. The results showed that the inhibition rates of SynB3PTX without an MMP2sensitive linker (PVGLIG) in U87MG and U251 were extremely low, at a nearzero level. Based on these observations, we confirmed that SynB3PVGLIGPTX has a specific antigrowth activity, that is, only in the presence of MMP2, the sensitive linker (PVGLIG) contained in SynB3PVGLIGPTX can be specifically hydrolyzed to release PTX, thereby inhibiting the proliferation of GBM cells."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	BALB/c athymic nude mice xenograft model.	Obtained from the Model Organism Data	High Expreesion	Tumor growth inhibition value (TGI)	91.50%	%	.	.	.	.	Glioblastoma	U-87MG cell	.	.	28 days	15 mg/5 mL kg<sup>-1</sup>	Bioluminescent imaging method	"While after the administration of SynB3PVGLIGPTX, there were few differences in the tumor signals between day 7 and day 14 (Figure 6A). At all later days, the differences in log (BLI) between the SynB3PVGLIGPTX and control group were significantly increased (***p < 0.001, Figure 6B), in which the mouse treated with SynB3PVGLIGPTX yielded a notably weaker bioluminescence radiance and a concurrently smaller bioluminescent area than those in the control group. On day 28, mice treated with SynB3PVGLIGPTX achieved the highest tumor inhibition rate (91.40&plusmn;0.57%), which was 2.27fold and 1.30fold higher than that of the PTX and TMZ groups, respectively (***p < 0.001, Figure 6C). From the results of the bioluminescence assays, we concluded that SynB3PVGLIGPTX could sufficiently suppress the growth of intracerebral tumors in vivo after 28 days compared with the inhibition rate yielded by TMZ or PTX (***p < 0.001, Figure 6C). In addition, the weight and overall survival period of mice administered with SynB3PVGLIGPTX (15 mg/5 mL kg-1, i.v.) were significantly higher than those in the control group (*p < 0.05, **p < 0.01, ***p < 0.001, Figure 6D,,E).E). Again, the separation in survival curves was notable among the four groups, with survival medians equal to 23, 29, and 25 for the control group, TMZ group and PTX group, respectively. In contrast, there was no death in the SynB3PVGLIGPTX group across the assays. Especially concerning was that, the administration concentration of SynB3PVGLIGPTX was 15 mg/5 mL kg-1, which is equivalent to 5.25 &mu;mol/5 mL kg-1. Theoretically, after SynB3PVGLIGPTX at this concentration is completely hydrolyzed by MMP2, the concentration of free PTX released is 4.49 mg/5 mL kg-1, which is only onethird of the concentration administered in the PTX group. The experimental results show that, compared with the group given a high dose of PTX (15 mg/5 mL kg-1), the tumor volume of mice given the nanoconjugate (SynB3PVGLIGPTX) was significantly reduced, and its overall survival was also significantly prolonged, which indicates that SynB3PVGLIGPTX has a significant antiglioma activity in vivo. Accordingly, SynB3PVGLIGPTX, as a PDC that combined PTX to a dualfunctional peptide consisting of SynB3 and a MMP2sensitive peptide, could observably improve survival and decrease weight loss over the PTX monotherapy in vivo, and significantly overmatched the mice treated with TMZ."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	BALB/c athymic nude mice xenograft model.	Obtained from the Model Organism Data	High Expreesion	Tumor growth inhibition value (TGI)	70.32%	%	.	.	.	.	Glioblastoma	U-87MG cell	.	.	21 days	15 mg/5 mL kg<sup>-1</sup>	Bioluminescent imaging method	"While after the administration of SynB3PVGLIGPTX, there were few differences in the tumor signals between day 7 and day 14 (Figure 6A). At all later days, the differences in log (BLI) between the SynB3PVGLIGPTX and control group were significantly increased (***p < 0.001, Figure 6B), in which the mouse treated with SynB3PVGLIGPTX yielded a notably weaker bioluminescence radiance and a concurrently smaller bioluminescent area than those in the control group. On day 28, mice treated with SynB3PVGLIGPTX achieved the highest tumor inhibition rate (91.40&plusmn;0.57%), which was 2.27fold and 1.30fold higher than that of the PTX and TMZ groups, respectively (***p < 0.001, Figure 6C). From the results of the bioluminescence assays, we concluded that SynB3PVGLIGPTX could sufficiently suppress the growth of intracerebral tumors in vivo after 28 days compared with the inhibition rate yielded by TMZ or PTX (***p < 0.001, Figure 6C). In addition, the weight and overall survival period of mice administered with SynB3PVGLIGPTX (15 mg/5 mL kg-1, i.v.) were significantly higher than those in the control group (*p < 0.05, **p < 0.01, ***p < 0.001, Figure 6D,,E).E). Again, the separation in survival curves was notable among the four groups, with survival medians equal to 23, 29, and 25 for the control group, TMZ group and PTX group, respectively. In contrast, there was no death in the SynB3PVGLIGPTX group across the assays. Especially concerning was that, the administration concentration of SynB3PVGLIGPTX was 15 mg/5 mL kg-1, which is equivalent to 5.25 &mu;mol/5 mL kg-1. Theoretically, after SynB3PVGLIGPTX at this concentration is completely hydrolyzed by MMP2, the concentration of free PTX released is 4.49 mg/5 mL kg-1, which is only onethird of the concentration administered in the PTX group. The experimental results show that, compared with the group given a high dose of PTX (15 mg/5 mL kg-1), the tumor volume of mice given the nanoconjugate (SynB3PVGLIGPTX) was significantly reduced, and its overall survival was also significantly prolonged, which indicates that SynB3PVGLIGPTX has a significant antiglioma activity in vivo. Accordingly, SynB3PVGLIGPTX, as a PDC that combined PTX to a dualfunctional peptide consisting of SynB3 and a MMP2sensitive peptide, could observably improve survival and decrease weight loss over the PTX monotherapy in vivo, and significantly overmatched the mice treated with TMZ."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00587	PDC_02063	Glioblastoma	BALB/c athymic nude mice xenograft model.	Obtained from the Model Organism Data	High Expreesion	Tumor growth inhibition value (TGI)	68.20%	%	.	.	.	.	Glioblastoma	U-87MG cell	.	.	14 days	15 mg/5 mL kg<sup>-1</sup>	Bioluminescent imaging method	"While after the administration of SynB3PVGLIGPTX, there were few differences in the tumor signals between day 7 and day 14 (Figure 6A). At all later days, the differences in log (BLI) between the SynB3PVGLIGPTX and control group were significantly increased (***p < 0.001, Figure 6B), in which the mouse treated with SynB3PVGLIGPTX yielded a notably weaker bioluminescence radiance and a concurrently smaller bioluminescent area than those in the control group. On day 28, mice treated with SynB3PVGLIGPTX achieved the highest tumor inhibition rate (91.40&plusmn;0.57%), which was 2.27fold and 1.30fold higher than that of the PTX and TMZ groups, respectively (***p < 0.001, Figure 6C). From the results of the bioluminescence assays, we concluded that SynB3PVGLIGPTX could sufficiently suppress the growth of intracerebral tumors in vivo after 28 days compared with the inhibition rate yielded by TMZ or PTX (***p < 0.001, Figure 6C). In addition, the weight and overall survival period of mice administered with SynB3PVGLIGPTX (15 mg/5 mL kg-1, i.v.) were significantly higher than those in the control group (*p < 0.05, **p < 0.01, ***p < 0.001, Figure 6D,,E).E). Again, the separation in survival curves was notable among the four groups, with survival medians equal to 23, 29, and 25 for the control group, TMZ group and PTX group, respectively. In contrast, there was no death in the SynB3PVGLIGPTX group across the assays. Especially concerning was that, the administration concentration of SynB3PVGLIGPTX was 15 mg/5 mL kg-1, which is equivalent to 5.25 &mu;mol/5 mL kg-1. Theoretically, after SynB3PVGLIGPTX at this concentration is completely hydrolyzed by MMP2, the concentration of free PTX released is 4.49 mg/5 mL kg-1, which is only onethird of the concentration administered in the PTX group. The experimental results show that, compared with the group given a high dose of PTX (15 mg/5 mL kg-1), the tumor volume of mice given the nanoconjugate (SynB3PVGLIGPTX) was significantly reduced, and its overall survival was also significantly prolonged, which indicates that SynB3PVGLIGPTX has a significant antiglioma activity in vivo. Accordingly, SynB3PVGLIGPTX, as a PDC that combined PTX to a dualfunctional peptide consisting of SynB3 and a MMP2sensitive peptide, could observably improve survival and decrease weight loss over the PTX monotherapy in vivo, and significantly overmatched the mice treated with TMZ."	"SynB3PVGLIGPTX, was designed, screened, and synthetized, in which PTX was combined with CPPs (e.g., SynB3) through an MMP2sensitive linker (PVGLIG). This peptidedrug complex exhibits three advantages as follows: 1) the constructed structure of CPPs should help enhance the permeability of PTXcontaining nanocomplex across the BBB; 2) this nanocomplex covers a MMP2sensitive linker between CPPs and PTX, making it possible to release the drug at the target site with high MMP2 expression level; and 3) the novel dualfunctional PTX prodrug is a watersoluble nanocomplex, which can overcome the side effect exerted by low solubility and formulating agent (Cremophore EL) of PTX."
REF00586	PDC_02064	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	3.8 &plusmn; 0.3 nM	nM	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	.	.	MTT assay	"LTP-1 exhibited greater anti-proliferative effects (IC50s of 3.8-20.3 nM) than PTX (IC50s of 6.6-28.6 nM) against most cancer cells except Hela, and less cytotoxicity to normal cells (IC50s of >80 nM and 66.0 nM for NCM460 and HEK-293, respectively). Thus, LTP-1 displayed not only enhanced anti-proliferative activity, but also higher selectivity for cancer cells over normal cells. It is also worthy of note that LTP-1 showed much higher activity against the paclitaxel-resistant A2780/PTX cells with an IC50 of 0.8 &mu;M, as compared to PTX which is essentially inactive (IC50 = 23.9 &mu;M). Hemolysis assay further testified that LTP-1 presented weak hemolytic activity even at a concentration up to 80 &mu;M (as illustrated in Fig. 4a)."	"LHRH, also named gonadotropin-releasing hormone (GnRH), is an endogenous peptide agonist (primary sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) released from hypothalamus. LHRH-R (LHRH receptor), a member of the G protein-coupled receptor family, is overexpressed in various tumor types, while their expression in the corresponding normal tissues, apart from pituitary cells, is comparatively low. Given this, we chose LHRH as the TTP component of MSCPTP (TTP-CPP peptide). In this investigation, we combined LHRH (as the TTP part), peptide PLGLAG, T2 (as the CPP part) and cysteine (as linker binding site) into an MSCPTP named LT-1. Then PTX was conjugated with LT-1 via a GSH-cleavable module to produce the smart PDC, namely LTP-1 (TTP-CPP-PTX conjugate). In vitro, LTP-1 exhibited selective and stronger cytotoxicity than PTX against LHRH-R-positive tumor cells with little effect on normal cells. In vivo, LTP-1 was highly effective in suppressing tumor growth in an MCF-7 xenograft mouse model. Additional experiments on both cellular and molecular levels were carried out to unravel the possible antitumor mechanism of action of LTP-1."
REF00586	PDC_02064	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	20.3 &plusmn; 3.3 nM	nM	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	.	.	.	MTT assay	"LTP-1 exhibited greater anti-proliferative effects (IC50s of 3.8-20.3 nM) than PTX (IC50s of 6.6-28.6 nM) against most cancer cells except Hela, and less cytotoxicity to normal cells (IC50s of >80 nM and 66.0 nM for NCM460 and HEK-293, respectively). Thus, LTP-1 displayed not only enhanced anti-proliferative activity, but also higher selectivity for cancer cells over normal cells. It is also worthy of note that LTP-1 showed much higher activity against the paclitaxel-resistant A2780/PTX cells with an IC50 of 0.8 &mu;M, as compared to PTX which is essentially inactive (IC50 = 23.9 &mu;M). Hemolysis assay further testified that LTP-1 presented weak hemolytic activity even at a concentration up to 80 &mu;M (as illustrated in Fig. 4a)."	"LHRH, also named gonadotropin-releasing hormone (GnRH), is an endogenous peptide agonist (primary sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) released from hypothalamus. LHRH-R (LHRH receptor), a member of the G protein-coupled receptor family, is overexpressed in various tumor types, while their expression in the corresponding normal tissues, apart from pituitary cells, is comparatively low. Given this, we chose LHRH as the TTP component of MSCPTP (TTP-CPP peptide). In this investigation, we combined LHRH (as the TTP part), peptide PLGLAG, T2 (as the CPP part) and cysteine (as linker binding site) into an MSCPTP named LT-1. Then PTX was conjugated with LT-1 via a GSH-cleavable module to produce the smart PDC, namely LTP-1 (TTP-CPP-PTX conjugate). In vitro, LTP-1 exhibited selective and stronger cytotoxicity than PTX against LHRH-R-positive tumor cells with little effect on normal cells. In vivo, LTP-1 was highly effective in suppressing tumor growth in an MCF-7 xenograft mouse model. Additional experiments on both cellular and molecular levels were carried out to unravel the possible antitumor mechanism of action of LTP-1."
REF00586	PDC_02064	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	5.6 &plusmn; 0.2 nM	nM	.	.	.	.	Colon adenocarcinoma	HT-29 cell	.	.	.	.	MTT assay	"LTP-1 exhibited greater anti-proliferative effects (IC50s of 3.8-20.3 nM) than PTX (IC50s of 6.6-28.6 nM) against most cancer cells except Hela, and less cytotoxicity to normal cells (IC50s of >80 nM and 66.0 nM for NCM460 and HEK-293, respectively). Thus, LTP-1 displayed not only enhanced anti-proliferative activity, but also higher selectivity for cancer cells over normal cells. It is also worthy of note that LTP-1 showed much higher activity against the paclitaxel-resistant A2780/PTX cells with an IC50 of 0.8 &mu;M, as compared to PTX which is essentially inactive (IC50 = 23.9 &mu;M). Hemolysis assay further testified that LTP-1 presented weak hemolytic activity even at a concentration up to 80 &mu;M (as illustrated in Fig. 4a)."	"LHRH, also named gonadotropin-releasing hormone (GnRH), is an endogenous peptide agonist (primary sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) released from hypothalamus. LHRH-R (LHRH receptor), a member of the G protein-coupled receptor family, is overexpressed in various tumor types, while their expression in the corresponding normal tissues, apart from pituitary cells, is comparatively low. Given this, we chose LHRH as the TTP component of MSCPTP (TTP-CPP peptide). In this investigation, we combined LHRH (as the TTP part), peptide PLGLAG, T2 (as the CPP part) and cysteine (as linker binding site) into an MSCPTP named LT-1. Then PTX was conjugated with LT-1 via a GSH-cleavable module to produce the smart PDC, namely LTP-1 (TTP-CPP-PTX conjugate). In vitro, LTP-1 exhibited selective and stronger cytotoxicity than PTX against LHRH-R-positive tumor cells with little effect on normal cells. In vivo, LTP-1 was highly effective in suppressing tumor growth in an MCF-7 xenograft mouse model. Additional experiments on both cellular and molecular levels were carried out to unravel the possible antitumor mechanism of action of LTP-1."
REF00586	PDC_02064	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	8.3 &plusmn; 0.5 nM	nM	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	.	.	MTT assay	"LTP-1 exhibited greater anti-proliferative effects (IC50s of 3.8-20.3 nM) than PTX (IC50s of 6.6-28.6 nM) against most cancer cells except Hela, and less cytotoxicity to normal cells (IC50s of >80 nM and 66.0 nM for NCM460 and HEK-293, respectively). Thus, LTP-1 displayed not only enhanced anti-proliferative activity, but also higher selectivity for cancer cells over normal cells. It is also worthy of note that LTP-1 showed much higher activity against the paclitaxel-resistant A2780/PTX cells with an IC50 of 0.8 &mu;M, as compared to PTX which is essentially inactive (IC50 = 23.9 &mu;M). Hemolysis assay further testified that LTP-1 presented weak hemolytic activity even at a concentration up to 80 &mu;M (as illustrated in Fig. 4a)."	"LHRH, also named gonadotropin-releasing hormone (GnRH), is an endogenous peptide agonist (primary sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) released from hypothalamus. LHRH-R (LHRH receptor), a member of the G protein-coupled receptor family, is overexpressed in various tumor types, while their expression in the corresponding normal tissues, apart from pituitary cells, is comparatively low. Given this, we chose LHRH as the TTP component of MSCPTP (TTP-CPP peptide). In this investigation, we combined LHRH (as the TTP part), peptide PLGLAG, T2 (as the CPP part) and cysteine (as linker binding site) into an MSCPTP named LT-1. Then PTX was conjugated with LT-1 via a GSH-cleavable module to produce the smart PDC, namely LTP-1 (TTP-CPP-PTX conjugate). In vitro, LTP-1 exhibited selective and stronger cytotoxicity than PTX against LHRH-R-positive tumor cells with little effect on normal cells. In vivo, LTP-1 was highly effective in suppressing tumor growth in an MCF-7 xenograft mouse model. Additional experiments on both cellular and molecular levels were carried out to unravel the possible antitumor mechanism of action of LTP-1."
REF00586	PDC_02064	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	800 &plusmn; 100 nM	nM	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780/PTX cell	.	.	.	.	MTT assay	"LTP-1 exhibited greater anti-proliferative effects (IC50s of 3.8-20.3 nM) than PTX (IC50s of 6.6-28.6 nM) against most cancer cells except Hela, and less cytotoxicity to normal cells (IC50s of >80 nM and 66.0 nM for NCM460 and HEK-293, respectively). Thus, LTP-1 displayed not only enhanced anti-proliferative activity, but also higher selectivity for cancer cells over normal cells. It is also worthy of note that LTP-1 showed much higher activity against the paclitaxel-resistant A2780/PTX cells with an IC50 of 0.8 &mu;M, as compared to PTX which is essentially inactive (IC50 = 23.9 &mu;M). Hemolysis assay further testified that LTP-1 presented weak hemolytic activity even at a concentration up to 80 &mu;M (as illustrated in Fig. 4a)."	"LHRH, also named gonadotropin-releasing hormone (GnRH), is an endogenous peptide agonist (primary sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) released from hypothalamus. LHRH-R (LHRH receptor), a member of the G protein-coupled receptor family, is overexpressed in various tumor types, while their expression in the corresponding normal tissues, apart from pituitary cells, is comparatively low. Given this, we chose LHRH as the TTP component of MSCPTP (TTP-CPP peptide). In this investigation, we combined LHRH (as the TTP part), peptide PLGLAG, T2 (as the CPP part) and cysteine (as linker binding site) into an MSCPTP named LT-1. Then PTX was conjugated with LT-1 via a GSH-cleavable module to produce the smart PDC, namely LTP-1 (TTP-CPP-PTX conjugate). In vitro, LTP-1 exhibited selective and stronger cytotoxicity than PTX against LHRH-R-positive tumor cells with little effect on normal cells. In vivo, LTP-1 was highly effective in suppressing tumor growth in an MCF-7 xenograft mouse model. Additional experiments on both cellular and molecular levels were carried out to unravel the possible antitumor mechanism of action of LTP-1."
REF00586	PDC_02064	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	80.0 nM	nM	.	.	.	.	Normal	NCM460 cell	.	.	.	.	MTT assay	"LTP-1 exhibited greater anti-proliferative effects (IC50s of 3.8-20.3 nM) than PTX (IC50s of 6.6-28.6 nM) against most cancer cells except Hela, and less cytotoxicity to normal cells (IC50s of >80 nM and 66.0 nM for NCM460 and HEK-293, respectively). Thus, LTP-1 displayed not only enhanced anti-proliferative activity, but also higher selectivity for cancer cells over normal cells. It is also worthy of note that LTP-1 showed much higher activity against the paclitaxel-resistant A2780/PTX cells with an IC50 of 0.8 &mu;M, as compared to PTX which is essentially inactive (IC50 = 23.9 &mu;M). Hemolysis assay further testified that LTP-1 presented weak hemolytic activity even at a concentration up to 80 &mu;M (as illustrated in Fig. 4a)."	"LHRH, also named gonadotropin-releasing hormone (GnRH), is an endogenous peptide agonist (primary sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) released from hypothalamus. LHRH-R (LHRH receptor), a member of the G protein-coupled receptor family, is overexpressed in various tumor types, while their expression in the corresponding normal tissues, apart from pituitary cells, is comparatively low. Given this, we chose LHRH as the TTP component of MSCPTP (TTP-CPP peptide). In this investigation, we combined LHRH (as the TTP part), peptide PLGLAG, T2 (as the CPP part) and cysteine (as linker binding site) into an MSCPTP named LT-1. Then PTX was conjugated with LT-1 via a GSH-cleavable module to produce the smart PDC, namely LTP-1 (TTP-CPP-PTX conjugate). In vitro, LTP-1 exhibited selective and stronger cytotoxicity than PTX against LHRH-R-positive tumor cells with little effect on normal cells. In vivo, LTP-1 was highly effective in suppressing tumor growth in an MCF-7 xenograft mouse model. Additional experiments on both cellular and molecular levels were carried out to unravel the possible antitumor mechanism of action of LTP-1."
REF00586	PDC_02064	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	66.0 &plusmn; 8.3 nM	nM	.	.	.	.	Normal	HEK293 cell	.	.	.	.	MTT assay	"LTP-1 exhibited greater anti-proliferative effects (IC50s of 3.8-20.3 nM) than PTX (IC50s of 6.6-28.6 nM) against most cancer cells except Hela, and less cytotoxicity to normal cells (IC50s of >80 nM and 66.0 nM for NCM460 and HEK-293, respectively). Thus, LTP-1 displayed not only enhanced anti-proliferative activity, but also higher selectivity for cancer cells over normal cells. It is also worthy of note that LTP-1 showed much higher activity against the paclitaxel-resistant A2780/PTX cells with an IC50 of 0.8 &mu;M, as compared to PTX which is essentially inactive (IC50 = 23.9 &mu;M). Hemolysis assay further testified that LTP-1 presented weak hemolytic activity even at a concentration up to 80 &mu;M (as illustrated in Fig. 4a)."	"LHRH, also named gonadotropin-releasing hormone (GnRH), is an endogenous peptide agonist (primary sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) released from hypothalamus. LHRH-R (LHRH receptor), a member of the G protein-coupled receptor family, is overexpressed in various tumor types, while their expression in the corresponding normal tissues, apart from pituitary cells, is comparatively low. Given this, we chose LHRH as the TTP component of MSCPTP (TTP-CPP peptide). In this investigation, we combined LHRH (as the TTP part), peptide PLGLAG, T2 (as the CPP part) and cysteine (as linker binding site) into an MSCPTP named LT-1. Then PTX was conjugated with LT-1 via a GSH-cleavable module to produce the smart PDC, namely LTP-1 (TTP-CPP-PTX conjugate). In vitro, LTP-1 exhibited selective and stronger cytotoxicity than PTX against LHRH-R-positive tumor cells with little effect on normal cells. In vivo, LTP-1 was highly effective in suppressing tumor growth in an MCF-7 xenograft mouse model. Additional experiments on both cellular and molecular levels were carried out to unravel the possible antitumor mechanism of action of LTP-1."
REF00586	PDC_02064	Solid tumor	MCF-7 xenograft mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	77.20%	%	.	.	.	.	.	.	.	.	Every two days for 2 weeks	8 &mu;mol/kg	Tumor volume detection	"At the dose of 8 &mu;mol/kg, LTP-1 decreased the tumor volume and tumor weight by 77.2% and 67.1%."	"LHRH, also named gonadotropin-releasing hormone (GnRH), is an endogenous peptide agonist (primary sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) released from hypothalamus. LHRH-R (LHRH receptor), a member of the G protein-coupled receptor family, is overexpressed in various tumor types, while their expression in the corresponding normal tissues, apart from pituitary cells, is comparatively low. Given this, we chose LHRH as the TTP component of MSCPTP (TTP-CPP peptide). In this investigation, we combined LHRH (as the TTP part), peptide PLGLAG, T2 (as the CPP part) and cysteine (as linker binding site) into an MSCPTP named LT-1. Then PTX was conjugated with LT-1 via a GSH-cleavable module to produce the smart PDC, namely LTP-1 (TTP-CPP-PTX conjugate). In vitro, LTP-1 exhibited selective and stronger cytotoxicity than PTX against LHRH-R-positive tumor cells with little effect on normal cells. In vivo, LTP-1 was highly effective in suppressing tumor growth in an MCF-7 xenograft mouse model. Additional experiments on both cellular and molecular levels were carried out to unravel the possible antitumor mechanism of action of LTP-1."
REF00586	PDC_02064	Solid tumor	MCF-7 xenograft mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	67.10%	%	.	.	.	.	.	.	.	.	Every two days for 2 weeks	8 &mu;mol/kg	.	"At the dose of 8 &mu;mol/kg, LTP-1 decreased the tumor volume and tumor weight by 77.2% and 67.1%."	"LHRH, also named gonadotropin-releasing hormone (GnRH), is an endogenous peptide agonist (primary sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) released from hypothalamus. LHRH-R (LHRH receptor), a member of the G protein-coupled receptor family, is overexpressed in various tumor types, while their expression in the corresponding normal tissues, apart from pituitary cells, is comparatively low. Given this, we chose LHRH as the TTP component of MSCPTP (TTP-CPP peptide). In this investigation, we combined LHRH (as the TTP part), peptide PLGLAG, T2 (as the CPP part) and cysteine (as linker binding site) into an MSCPTP named LT-1. Then PTX was conjugated with LT-1 via a GSH-cleavable module to produce the smart PDC, namely LTP-1 (TTP-CPP-PTX conjugate). In vitro, LTP-1 exhibited selective and stronger cytotoxicity than PTX against LHRH-R-positive tumor cells with little effect on normal cells. In vivo, LTP-1 was highly effective in suppressing tumor growth in an MCF-7 xenograft mouse model. Additional experiments on both cellular and molecular levels were carried out to unravel the possible antitumor mechanism of action of LTP-1."
REF00586	PDC_02064	Solid tumor	MCF-7 xenograft mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	90.10%	%	.	.	.	.	.	.	.	.	Every two days for 2 weeks	12 &mu;mol/kg	Tumor volume detection	"At the dose of 12 &mu;mol/kg, LTP-1 decreased the tumor volume and tumor weight by 90.1% and 83.4%, respectively."	"LHRH, also named gonadotropin-releasing hormone (GnRH), is an endogenous peptide agonist (primary sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) released from hypothalamus. LHRH-R (LHRH receptor), a member of the G protein-coupled receptor family, is overexpressed in various tumor types, while their expression in the corresponding normal tissues, apart from pituitary cells, is comparatively low. Given this, we chose LHRH as the TTP component of MSCPTP (TTP-CPP peptide). In this investigation, we combined LHRH (as the TTP part), peptide PLGLAG, T2 (as the CPP part) and cysteine (as linker binding site) into an MSCPTP named LT-1. Then PTX was conjugated with LT-1 via a GSH-cleavable module to produce the smart PDC, namely LTP-1 (TTP-CPP-PTX conjugate). In vitro, LTP-1 exhibited selective and stronger cytotoxicity than PTX against LHRH-R-positive tumor cells with little effect on normal cells. In vivo, LTP-1 was highly effective in suppressing tumor growth in an MCF-7 xenograft mouse model. Additional experiments on both cellular and molecular levels were carried out to unravel the possible antitumor mechanism of action of LTP-1."
REF00586	PDC_02064	Solid tumor	MCF-7 xenograft mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	83.40%	%	.	.	.	.	.	.	.	.	Every two days for 2 weeks	12 &mu;mol/kg	.	"At the dose of 12 &mu;mol/kg, LTP-1 decreased the tumor volume and tumor weight by 90.1% and 83.4%, respectively."	"LHRH, also named gonadotropin-releasing hormone (GnRH), is an endogenous peptide agonist (primary sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) released from hypothalamus. LHRH-R (LHRH receptor), a member of the G protein-coupled receptor family, is overexpressed in various tumor types, while their expression in the corresponding normal tissues, apart from pituitary cells, is comparatively low. Given this, we chose LHRH as the TTP component of MSCPTP (TTP-CPP peptide). In this investigation, we combined LHRH (as the TTP part), peptide PLGLAG, T2 (as the CPP part) and cysteine (as linker binding site) into an MSCPTP named LT-1. Then PTX was conjugated with LT-1 via a GSH-cleavable module to produce the smart PDC, namely LTP-1 (TTP-CPP-PTX conjugate). In vitro, LTP-1 exhibited selective and stronger cytotoxicity than PTX against LHRH-R-positive tumor cells with little effect on normal cells. In vivo, LTP-1 was highly effective in suppressing tumor growth in an MCF-7 xenograft mouse model. Additional experiments on both cellular and molecular levels were carried out to unravel the possible antitumor mechanism of action of LTP-1."
REF00585	PDC_02065	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	611 &plusmn; 80 nM	nM	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	.	.	.	"The most potent among them was found to be pro-drug GOXG2 with IC50 494 &plusmn; 93 nM and 675 &plusmn; 82 nM against DU145 and PC3, respectively. Regarding the other two conjugates, GN4OXG was found to be the next most cytotoxic compound against DU145 with IC50 590 &plusmn; 62 nM, followed by the least toxic GOXG1 with IC50 611 &plusmn; 80 nM. In contrast, GOXG1 was the second more toxic against PC3 with IC50 754 &plusmn; 142 nM, followed by the least toxic GN4OXG which showed IC50 833 &plusmn; 27 nM. The results are summarized in Table 2."	"We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA)."
REF00585	PDC_02065	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	754 &plusmn; 142 nM	nM	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"The most potent among them was found to be pro-drug GOXG2 with IC50 494 &plusmn; 93 nM and 675 &plusmn; 82 nM against DU145 and PC3, respectively. Regarding the other two conjugates, GN4OXG was found to be the next most cytotoxic compound against DU145 with IC50 590 &plusmn; 62 nM, followed by the least toxic GOXG1 with IC50 611 &plusmn; 80 nM. In contrast, GOXG1 was the second more toxic against PC3 with IC50 754 &plusmn; 142 nM, followed by the least toxic GN4OXG which showed IC50 833 &plusmn; 27 nM. The results are summarized in Table 2."	"We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA)."
REF00585	PDC_02066	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	494 &plusmn; 93 nM	nM	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	.	.	.	"The most potent among them was found to be pro-drug GOXG2 with IC50 494 &plusmn; 93 nM and 675 &plusmn; 82 nM against DU145 and PC3, respectively. Regarding the other two conjugates, GN4OXG was found to be the next most cytotoxic compound against DU145 with IC50 590 &plusmn; 62 nM, followed by the least toxic GOXG1 with IC50 611 &plusmn; 80 nM. In contrast, GOXG1 was the second more toxic against PC3 with IC50 754 &plusmn; 142 nM, followed by the least toxic GN4OXG which showed IC50 833 &plusmn; 27 nM. The results are summarized in Table 2."	"We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA)."
REF00585	PDC_02066	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	675 &plusmn; 82 nM	nM	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"The most potent among them was found to be pro-drug GOXG2 with IC50 494 &plusmn; 93 nM and 675 &plusmn; 82 nM against DU145 and PC3, respectively. Regarding the other two conjugates, GN4OXG was found to be the next most cytotoxic compound against DU145 with IC50 590 &plusmn; 62 nM, followed by the least toxic GOXG1 with IC50 611 &plusmn; 80 nM. In contrast, GOXG1 was the second more toxic against PC3 with IC50 754 &plusmn; 142 nM, followed by the least toxic GN4OXG which showed IC50 833 &plusmn; 27 nM. The results are summarized in Table 2."	"We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA)."
REF00585	PDC_02067	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	590 &plusmn; 62 nM	nM	.	.	.	.	Prostate carcinoma	DU145 cell	.	.	.	.	.	"The most potent among them was found to be pro-drug GOXG2 with IC50 494 &plusmn; 93 nM and 675 &plusmn; 82 nM against DU145 and PC3, respectively. Regarding the other two conjugates, GN4OXG was found to be the next most cytotoxic compound against DU145 with IC50 590 &plusmn; 62 nM, followed by the least toxic GOXG1 with IC50 611 &plusmn; 80 nM. In contrast, GOXG1 was the second more toxic against PC3 with IC50 754 &plusmn; 142 nM, followed by the least toxic GN4OXG which showed IC50 833 &plusmn; 27 nM. The results are summarized in Table 2."	"We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA)."
REF00585	PDC_02067	Prostate cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	833 &plusmn; 27 nM	nM	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"The most potent among them was found to be pro-drug GOXG2 with IC50 494 &plusmn; 93 nM and 675 &plusmn; 82 nM against DU145 and PC3, respectively. Regarding the other two conjugates, GN4OXG was found to be the next most cytotoxic compound against DU145 with IC50 590 &plusmn; 62 nM, followed by the least toxic GOXG1 with IC50 611 &plusmn; 80 nM. In contrast, GOXG1 was the second more toxic against PC3 with IC50 754 &plusmn; 142 nM, followed by the least toxic GN4OXG which showed IC50 833 &plusmn; 27 nM. The results are summarized in Table 2."	"We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA)."
REF00584	PDC_00239	Multiple myeloma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	0.05 &mu;M	&mu;M	.	.	.	.	Lung large cell carcinoma	U-1810 cell	.	.	.	.	.	"Compared with the known alkylator melphalan, melflufen had a higher cytotoxic activity in this broad range of malignant human cells, with a mean IC50 value that was 35-fold lower with melflufen than melphalan."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	31.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	28-day cycle	40 mg with dexamethasone (40 mg)	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	5.7 months	months	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	28-day cycle	40 mg with dexamethasone (40 mg)	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Adverse event rate	100.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	28-day cycle	40 mg with dexamethasone (40 mg)	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 treatment-emergent adverse event	82%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	28-day cycle	40 mg with dexamethasone (40 mg)	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Rate of adverse events	38%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	28-day cycle	40 mg with dexamethasone (40 mg)	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	27.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	28-day cycle	40 mg with dexamethasone (40 mg)	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	29.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	14.3 week (median)	40 mg with dexamethasone (40 mg)	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	4.2 months	months	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	14.3 week (median)	40 mg with dexamethasone (40 mg)	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Adverse event rate	97.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	14.3 week (median)	40 mg with dexamethasone (40 mg)	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade 3/4 adverse events	85%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	14.3 week (median)	40 mg with dexamethasone (40 mg)	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	76.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	6.2 month (median)	30 or 40 mg	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	14.3 months	months	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	6.2 month (median)	30 or 40 mg	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	82.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	6.2 month (median)	30 or 40 mg	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Rate of adverse events	36%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	6.2 month (median)	30 or 40 mg	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	18.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	6.2 month (median)	30 or 40 mg	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	67%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	9.3 month (median)	30 or 40 mg	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	Not reached	.	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	9.3 month (median)	30 or 40 mg	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Rate of adverse events	83%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	9.3 month (median)	30 or 40 mg	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Treatment-emergent adverse event	17.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	9.3 month (median)	30 or 40 mg	.	.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	8.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	.	.	.	"Among the 13 patients who received single-agent melflufen, the median number of prior therapies was 5 (range, 4-8), the ORR was 8% (1 PR), median PFS was 4.4 months, and median OS was 15.5 months. "	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	4.4 months	months	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	.	.	.	"Among the 13 patients who received single-agent melflufen, the median number of prior therapies was 5 (range, 4-8), the ORR was 8% (1 PR), median PFS was 4.4 months, and median OS was 15.5 months. "	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	15.5 months	months	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	.	.	.	"Among the 13 patients who received single-agent melflufen, the median number of prior therapies was 5 (range, 4-8), the ORR was 8% (1 PR), median PFS was 4.4 months, and median OS was 15.5 months. "	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Thrombocytopenia	73.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	.	.	.	"Melflufen plus dexamethasone was generally manageable in this heavily pretreated patient population [51]. All patients experienced &ge;1 AE, most commonly hematologic AEs including thrombocytopenia (73%), neutropenia (69%), and anemia (64%). The most common non-hematologic AEs included pyrexia (40%), asthenia (31%), fatigue (29%), nausea (27%), and diarrhea (24%). "	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Neutropenia	69.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	.	.	.	"Melflufen plus dexamethasone was generally manageable in this heavily pretreated patient population [51]. All patients experienced &ge;1 AE, most commonly hematologic AEs including thrombocytopenia (73%), neutropenia (69%), and anemia (64%). The most common non-hematologic AEs included pyrexia (40%), asthenia (31%), fatigue (29%), nausea (27%), and diarrhea (24%). "	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Anemia	64.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	.	.	.	"Melflufen plus dexamethasone was generally manageable in this heavily pretreated patient population [51]. All patients experienced &ge;1 AE, most commonly hematologic AEs including thrombocytopenia (73%), neutropenia (69%), and anemia (64%). The most common non-hematologic AEs included pyrexia (40%), asthenia (31%), fatigue (29%), nausea (27%), and diarrhea (24%). "	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Pyrexia	40%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	.	.	.	"Melflufen plus dexamethasone was generally manageable in this heavily pretreated patient population [51]. All patients experienced &ge;1 AE, most commonly hematologic AEs including thrombocytopenia (73%), neutropenia (69%), and anemia (64%). The most common non-hematologic AEs included pyrexia (40%), asthenia (31%), fatigue (29%), nausea (27%), and diarrhea (24%). "	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Asthenia	31.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	.	.	.	"Melflufen plus dexamethasone was generally manageable in this heavily pretreated patient population [51]. All patients experienced &ge;1 AE, most commonly hematologic AEs including thrombocytopenia (73%), neutropenia (69%), and anemia (64%). The most common non-hematologic AEs included pyrexia (40%), asthenia (31%), fatigue (29%), nausea (27%), and diarrhea (24%). "	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Fatigue	29%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	.	.	.	"Melflufen plus dexamethasone was generally manageable in this heavily pretreated patient population [51]. All patients experienced &ge;1 AE, most commonly hematologic AEs including thrombocytopenia (73%), neutropenia (69%), and anemia (64%). The most common non-hematologic AEs included pyrexia (40%), asthenia (31%), fatigue (29%), nausea (27%), and diarrhea (24%). "	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Nausea	27.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	.	.	.	"Melflufen plus dexamethasone was generally manageable in this heavily pretreated patient population [51]. All patients experienced &ge;1 AE, most commonly hematologic AEs including thrombocytopenia (73%), neutropenia (69%), and anemia (64%). The most common non-hematologic AEs included pyrexia (40%), asthenia (31%), fatigue (29%), nausea (27%), and diarrhea (24%). "	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Diarrhea	24.00%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	.	.	.	"Melflufen plus dexamethasone was generally manageable in this heavily pretreated patient population [51]. All patients experienced &ge;1 AE, most commonly hematologic AEs including thrombocytopenia (73%), neutropenia (69%), and anemia (64%). The most common non-hematologic AEs included pyrexia (40%), asthenia (31%), fatigue (29%), nausea (27%), and diarrhea (24%). "	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Grade &ge;3 adverse event	82%	%	.	.	.	Patients with multi-refractory multiple myeloma.	.	.	.	.	.	.	.	Melflufen-related Grade &ge;3 AEs occurred in 82% of patients.	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	29.00%	%	.	.	.	Patients evaluable for response.	.	.	.	.	.	.	.	"Among 125 patients evaluable for response, the ORR (&ge;PR) was 29%, with 1 patient achieving a stringent complete response (CR) and 10 patients achieving a VGPR. The median duration of response was 4.4 months. The ORR was 21% among 47 patients with high-risk cytogenetics, 24% among 93 patients with triple-class refractory disease, and 24% among 42 patients with extramedullary disease."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median duration of response	4.4 months	months	.	.	.	Patients evaluable for response.	.	.	.	.	.	.	.	"Among 125 patients evaluable for response, the ORR (&ge;PR) was 29%, with 1 patient achieving a stringent complete response (CR) and 10 patients achieving a VGPR. The median duration of response was 4.4 months. The ORR was 21% among 47 patients with high-risk cytogenetics, 24% among 93 patients with triple-class refractory disease, and 24% among 42 patients with extramedullary disease."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	21.00%	%	.	.	.	Patients with high-risk cytogenetics.	.	.	.	.	.	.	.	"Among 125 patients evaluable for response, the ORR (&ge;PR) was 29%, with 1 patient achieving a stringent complete response (CR) and 10 patients achieving a VGPR. The median duration of response was 4.4 months. The ORR was 21% among 47 patients with high-risk cytogenetics, 24% among 93 patients with triple-class refractory disease, and 24% among 42 patients with extramedullary disease."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	24.00%	%	.	.	.	Patients with triple-class refractory disease.	.	.	.	.	.	.	.	"Among 125 patients evaluable for response, the ORR (&ge;PR) was 29%, with 1 patient achieving a stringent complete response (CR) and 10 patients achieving a VGPR. The median duration of response was 4.4 months. The ORR was 21% among 47 patients with high-risk cytogenetics, 24% among 93 patients with triple-class refractory disease, and 24% among 42 patients with extramedullary disease."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Overall response rate (ORR)	24.00%	%	.	.	.	Patients with extramedullary disease.	.	.	.	.	.	.	.	"Among 125 patients evaluable for response, the ORR (&ge;PR) was 29%, with 1 patient achieving a stringent complete response (CR) and 10 patients achieving a VGPR. The median duration of response was 4.4 months. The ORR was 21% among 47 patients with high-risk cytogenetics, 24% among 93 patients with triple-class refractory disease, and 24% among 42 patients with extramedullary disease."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	4.2 months	months	.	.	.	All patients.	.	.	.	.	.	.	.	"The median PFS and OS were 4.2 and 11.6 months for all patients, 4.0 and 11.3 months for patients with triple-class refractory disease, and 3.0 and 8.1 months for patients with extramedullary disease, respectively."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	11.6 months	months	.	.	.	All patients.	.	.	.	.	.	.	.	"The median PFS and OS were 4.2 and 11.6 months for all patients, 4.0 and 11.3 months for patients with triple-class refractory disease, and 3.0 and 8.1 months for patients with extramedullary disease, respectively."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	4.0 months	months	.	.	.	Patients with triple-class refractory disease.	.	.	.	.	.	.	.	"The median PFS and OS were 4.2 and 11.6 months for all patients, 4.0 and 11.3 months for patients with triple-class refractory disease, and 3.0 and 8.1 months for patients with extramedullary disease, respectively."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	11.3 months	months	.	.	.	Patients with triple-class refractory disease.	.	.	.	.	.	.	.	"The median PFS and OS were 4.2 and 11.6 months for all patients, 4.0 and 11.3 months for patients with triple-class refractory disease, and 3.0 and 8.1 months for patients with extramedullary disease, respectively."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median progression-free survival (mPFS)	3.0 months	months	.	.	.	Patients with extramedullary disease.	.	.	.	.	.	.	.	"The median PFS and OS were 4.2 and 11.6 months for all patients, 4.0 and 11.3 months for patients with triple-class refractory disease, and 3.0 and 8.1 months for patients with extramedullary disease, respectively."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	.	Identified from the Human Clinical Data	High Expreesion	Median overall survival (mOS)	8.1 months	months	.	.	.	Patients with extramedullary disease.	.	.	.	.	.	.	.	"The median PFS and OS were 4.2 and 11.6 months for all patients, 4.0 and 11.3 months for patients with triple-class refractory disease, and 3.0 and 8.1 months for patients with extramedullary disease, respectively."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	75 patients with multiple myeloma.	Identified from the Human Clinical Data	High Expreesion	Adverse event rate	97.00%	%	.	.	.	.	.	.	.	.	.	.	.	"Overall, 97% of patients experienced any-grade AEs and 85% of patients experienced Grades 3/4 AEs."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00584	PDC_00239	Multiple myeloma	75 patients with multiple myeloma.	Identified from the Human Clinical Data	High Expreesion	Grade 3/4 adverse events	85%	%	.	.	.	.	.	.	.	.	.	.	.	"Overall, 97% of patients experienced any-grade AEs and 85% of patients experienced Grades 3/4 AEs."	"Melflufen is highly lipophilic, which promotes its rapid uptake by cells. Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases). Aminopeptidases are Zn2+-dependent metalloproteinases that remove amino acids at the N-terminal position from oligopeptides and have been associated with multiple tumorigenic processes such as proliferation, apoptosis, differentiation, angiogenesis, and motility. The dependence of melflufen on aminopeptidases was initially demonstrated by the reduced cytotoxic activity of melflufen-but not the alkylator melphalan-when cells were pretreated with bestatin, an antibiotic that is a potent aminopeptidase inhibitor. In addition, structure analogs designed to resist peptide hydrolysis (N-methyl derivative and derivative with D-amino acid) were shown to be almost 100-fold less potent than melflufen. Subsequent in vitro studies demonstrated that hydrolytic cleavage of melflufen by aminopeptidases releases alkylator payloads, including melphalan. In vitro, the activity of melflufen is multi-pronged, including induction of DNA damage, induction of apoptosis, inhibition of VEGF-dependent cell migration, and inhibition of tumor-associated angiogenesis, which have been further reviewed elsewhere. Downregulation of aminopeptidases resulted in reduced melflufen-mediated cytotoxic activity and apoptotic signaling in cultured cells."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	78.00%	%	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	7.8 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	60.00%	%	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	15.6 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	35.00%	%	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	31.3 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	30.00%	%	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	62.5 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	28.00%	%	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	125 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	20.00%	%	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	250 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	15.00%	%	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	500 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	64.00%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	7.8 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	62.00%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	15.6 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	60.00%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	31.3 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	55.00%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	62.5 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	30.00%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	125 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	20.00%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	250 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	15.00%	%	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	500 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	83.00%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	7.8 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	80.00%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	15.6 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	78.00%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	31.3 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	70.00%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	62.5 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	50.00%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	125 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	40.00%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	250 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	20.00%	%	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	48 h	500 &mu;M	MTT assay	CRB and CRB-FFFK-cyclen hydrogel both exhibited broad-spectrum anticancer activities against different types of cancer cells in a dose-dependent manner.	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	23.8 &mu;M	&mu;M	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	.	.	MTT assay	"The IC50 values of CRB-FFFK-cyclen nanofiber against A549 cells, HeLa cells and MCF-7 cells were 23.8, 50.2, and 127.4 &mu;M, respectively."	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	50.2 &mu;M	&mu;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	.	.	MTT assay	"The IC50 values of CRB-FFFK-cyclen nanofiber against A549 cells, HeLa cells and MCF-7 cells were 23.8, 50.2, and 127.4 &mu;M, respectively."	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00583	PDC_02068	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	127.4 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"After incubation for 6 h, the NBD-FFFK-cyclen hydrogel exhibited much stronger green fluorescence than NBD-FFFK in A549 cells, indicating that the NBD-FFFK-cyclen hydrogel was more easily taken up by A549 cells than NBD-FFFK. We also quantified the cellular uptake of NBD-FFFK and NBD-FFFK-cyclen using a flow cytometer based on the intensity of fluorescence. The result showed that the cellular uptake of NBD-FFFK-cyclen is much greater than that of NBD-FFFK at 1 h, 3 h, and 6 h (Fig. S9). In terms of structure, NBD-FFFK-cyclen contained a macrocyclic polyamine cyclen fragment, which could be protonated in a tumor environment and resulted in a cationic NBD-FFFK-cyclen hydrogel. The resulting cationic hydrogel has high affinity to a negatively charged cell membrane, which could greatly improve the cellular uptake of the hydrogel."	.	.	MTT assay	"The IC50 values of CRB-FFFK-cyclen nanofiber against A549 cells, HeLa cells and MCF-7 cells were 23.8, 50.2, and 127.4 &mu;M, respectively."	"The DNA-alkylating agent chlorambucil (CRB) belongs to aryl nitrogen mustard antitumor drugs, and has been widely used for treating different types of cancerous diseases. However, the clinical application of CRB is severely restricted by its poor aqueous solubility, lack of targeting, short degradation half-life and severe side effects. Macrocyclic polyamines have many applications in medicine, industry and other fields, owing to their chemical and biological properties. Some of them, such as cyclen and cyclam, could be protonated below physiological pH (7.4), and the lower the pH, the higher the degree of protonation. It is reported that the pH of the tumor environment is lower than the physiological pH, which is beneficial to the protonation of macrocyclic polyamines. Modification of macrocyclic polyamine to self-assembling peptide-drug amphiphiles can increase the cell accumulation of the hydrogel, because the cationic hydrogel has a high affinity to a negatively charged cell membrane and nucleus. Therefore, a macrocyclic polyamine containing peptide hydrogel could serve as a suitable delivery system to improve the pharmacokinetic properties of CRB, achieving improved delivery efficacy and enhanced antitumor activity without severe side effects. Herein, we report a self-assembling peptide-based cationic supramolecular nanomedicine bearing the small molecule agent CRB and macrocyclic polyamine cyclen. We found that the CRB-FFFK-cyclen conjugate could readily transform into a hydrogel through a heating-cooling process, and the resulting hydrogel could significantly improve drug stability, cellular uptake and, antitumor activity."
REF00582	PDC_02069	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	84%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	0.1 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02069	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	63%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	1 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02069	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	58%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	2.5 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02069	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	50%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	5 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02069	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	48%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	10 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02069	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	40%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	25 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02069	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	38%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	50 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02069	Hepatocellular carcinoma	H22 tumor-bearing C57BL/6 mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumer volume	580 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	18 days	11 mg/kg	.	"For the control group receiving PBS injections, the tumor volume expanded rapidly, whereas the tumor growth of the group receiving free DOX, PDC-DOX2, and HA@PDC-DOX2 could be suppressed to some degree. Among them, the inhibition in the HA@PDC-DOX2 group was the most obvious. "	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02069	Hepatocellular carcinoma	H22 tumor-bearing C57BL/6 mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Body weight	19g	g	.	.	.	.	.	.	.	.	18 days	11 mg/kg	.	"Body weight changes in all of the C57BL/6 mice in treatment groups, presented steady decreases."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02070	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	78%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	0.1 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02070	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	75%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	1 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02070	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	72%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	2.5 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02070	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	70%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	5 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02070	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	60%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	10 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02070	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	50%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	25 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02070	Hepatocellular carcinoma	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	40%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	4 h	50 &mu;g/ml	MTT assay	"All of the samples inhibited tumor cell activity in a dose-dependent manner (0.1-50 &mu;g/mL).The antitumor activity of PDC-DOX2 and HA@PDC-DOX2 was lower than that of free DOX (IC50 of DOX: 3.102 &mu;g/mL, IC50 of PDC-DOX2: 7.449 &mu;g/mL, IC50 of HA@PDC-DOX2: 24.05 &mu;g/mL)."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02070	Hepatocellular carcinoma	H22 tumor-bearing C57BL/6 mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumer volume	550 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	18 days	11 mg/kg	.	"For the control group receiving PBS injections, the tumor volume expanded rapidly, whereas the tumor growth of the group receiving free DOX, PDC-DOX2, and HA@PDC-DOX2 could be suppressed to some degree. Among them, the inhibition in the HA@PDC-DOX2 group was the most obvious. "	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00582	PDC_02070	Hepatocellular carcinoma	H22 tumor-bearing C57BL/6 mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Body weight	19g	g	.	.	.	.	.	.	.	.	18 days	11 mg/kg	.	"Body weight changes in all of the C57BL/6 mice in treatment groups, presented steady decreases."	"In this study, we designed and synthesized a novel peptide-drug conjugate (PDC-DOX2), in which two doxorubicin (DOX) molecules are covalently linked to a modified peptide with two carboxyl groups (Pep-AA). In neutral aqueous solution, PDC-DOX2 can self-assemble into stable spherical micelles due to hydrophilic-hydrophobic interactions. The sphere morphology can provide for the feasibility of intravenous injections of such peptide drug conjugates. PDC-DOX2 nanomicelles are stable spherical structures under neutral conditions, while they aggregate with decreased pH values. The pH value affected the assembly performance of PDC-DOX2 to a certain extent. With a decrease in pH (from a neutral to an acid environment), the morphology transforms from independent nanomicelles to slightly aggregated micelles and then to very aggregate micelles with diameters of nearly 3000 nm. The surfaces of PDC-DOX2 micelles were positively charged due to the lysine and arginine residues in the peptides. To avoid being engulfed by macrophages in plasma and prolong their blood circulation time, we further coated the positively charged micelles with a negatively charged natural polysaccharide shell, hyaluronic acid (HA), to form core-shell structure nanomedicine HA@PDC-DOX2. HA has various advantages, such as biodegradability, non-inflammatory, and non-immunogenicity. In addition, HA-coated nanomicelles allow for enhanced targeting in cancer therapy because HA can interact with overexpressed receptors in cancer cells, such as cluster determinant 44 (CD44), receptor for hyaluronic acid mediated motility (RHAMM) and intercellular adhesion molecule 1 (ICAM-1). Particularly, we found that the amount of HA influences the properties of HA@PDC-DOX2. The particle size of HA@PDC-DOX2 decreases with increasing HA content. The amount of HA can regulate the particle size, and HA@PDC-DOX2 become more stable in solution due to eliminating electrostatic repulsion of PDC-DOX2. The schematic mechanism of HA@PDC-DOX2 is shown in Scheme 1. First, PDC-DOX2 self-assembles into nanomicelles in neutral aqueous solution. Then, HA@PDC-DOX2 is constructed by negative HA shells and positively PDC-DOX2 cores. HA@PDC-DOX2 can deliver DOX into tumor sites via passive and active targeting effects. The core-shell structure HA@PDC-DOX2 nanomedicine showed better treatment effects on hepatocellular carcinoma, compared with PDC-DOX2 micelles and free DOX."
REF00581	PDC_02071	Drug-resistant cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	7.53 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	"As a result, approximately 60% of the DD-NPs were detected in endosomes and about 40% was observed in the lysosomes, suggesting DD-NPs uptake through nanoparticle-derived endosomal/lysosomal pathwa."	.	.	.	"When both cells were treated with different concentrations of DD-NPs (0-186 &mu;g/ml), the cytotoxicity was induced only in MCF-7, showing similar cytotoxicity with free DOX at a high concentration (Fig. 2h). However, DD-NPs did not exhibit significant cytotoxicity in H9C2 whereas free DOX showed similar cytotoxicity when treated to MCF-7 (Fig. 2i). "	"These results suggest that the DD-NPs could improve the in vivo bioavailability and cancer targeting efficiency of SMAC via their stable nanoparticle-derived EPR effect, leading to effective IAPs inhibition in targeted tumor tissues. "
REF00581	PDC_02071	Drug-resistant cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	200 &mu;M	&mu;M	.	.	.	.	Normal	H9c2 cell	.	"As a result, approximately 60% of the DD-NPs were detected in endosomes and about 40% was observed in the lysosomes, suggesting DD-NPs uptake through nanoparticle-derived endosomal/lysosomal pathwa."	.	.	.	"When both cells were treated with different concentrations of DD-NPs (0-186 &mu;g/ml), the cytotoxicity was induced only in MCF-7, showing similar cytotoxicity with free DOX at a high concentration (Fig. 2h). However, DD-NPs did not exhibit significant cytotoxicity in H9C2 whereas free DOX showed similar cytotoxicity when treated to MCF-7 (Fig. 2i). "	"These results suggest that the DD-NPs could improve the in vivo bioavailability and cancer targeting efficiency of SMAC via their stable nanoparticle-derived EPR effect, leading to effective IAPs inhibition in targeted tumor tissues. "
REF00581	PDC_02071	Drug-resistant cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	9.2 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7/ADR cell	.	"As a result, approximately 60% of the DD-NPs were detected in endosomes and about 40% was observed in the lysosomes, suggesting DD-NPs uptake through nanoparticle-derived endosomal/lysosomal pathwa."	48 h	.	.	"However, DD-NP-treated group showed similar IC50 in wild-MCF-7 (7.53 &mu;M) and ADR-MCF-7 (9.2 &mu;M), due to the synergetic pro-apoptotic effect of SMAC molecules in DD-NPs (Fig. 3g)."	"These results suggest that the DD-NPs could improve the in vivo bioavailability and cancer targeting efficiency of SMAC via their stable nanoparticle-derived EPR effect, leading to effective IAPs inhibition in targeted tumor tissues. "
REF00581	PDC_02071	Drug-resistant cancer	MCF-7 tumor-bearing mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumer volume	10 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	"As a result, approximately 60% of the DD-NPs were detected in endosomes and about 40% was observed in the lysosomes, suggesting DD-NPs uptake through nanoparticle-derived endosomal/lysosomal pathwa."	21 days	.	.	.	"These results suggest that the DD-NPs could improve the in vivo bioavailability and cancer targeting efficiency of SMAC via their stable nanoparticle-derived EPR effect, leading to effective IAPs inhibition in targeted tumor tissues. "
REF00581	PDC_02071	Drug-resistant cancer	MCF-7 tumor-bearing mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Body weight	23.5g	g	.	.	.	.	.	.	.	"As a result, approximately 60% of the DD-NPs were detected in endosomes and about 40% was observed in the lysosomes, suggesting DD-NPs uptake through nanoparticle-derived endosomal/lysosomal pathwa."	13 days	.	.	.	"These results suggest that the DD-NPs could improve the in vivo bioavailability and cancer targeting efficiency of SMAC via their stable nanoparticle-derived EPR effect, leading to effective IAPs inhibition in targeted tumor tissues. "
REF00581	PDC_02071	Drug-resistant cancer	MCF-7 tumor-bearing mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	76.00%	%	.	.	.	.	.	.	.	"As a result, approximately 60% of the DD-NPs were detected in endosomes and about 40% was observed in the lysosomes, suggesting DD-NPs uptake through nanoparticle-derived endosomal/lysosomal pathwa."	.	1 mg/kg of DOX	.	"Finally, the tumor volumes were successfully suppressed from 76% to 89% when the intravenous dose of DD-NPs increased from 1 mg/kg of DOX to 5 mg/kg of DOX."	"These results suggest that the DD-NPs could improve the in vivo bioavailability and cancer targeting efficiency of SMAC via their stable nanoparticle-derived EPR effect, leading to effective IAPs inhibition in targeted tumor tissues. "
REF00581	PDC_02071	Drug-resistant cancer	MCF-7 tumor-bearing mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor growth inhibition value (TGI)	89%-99%	%	.	.	.	.	.	.	.	"As a result, approximately 60% of the DD-NPs were detected in endosomes and about 40% was observed in the lysosomes, suggesting DD-NPs uptake through nanoparticle-derived endosomal/lysosomal pathwa."	.	5 mg/kg	.	"Finally, the tumor volumes were successfully suppressed from 76% to 89% when the intravenous dose of DD-NPs increased from 1 mg/kg of DOX to 5 mg/kg of DOX."	"These results suggest that the DD-NPs could improve the in vivo bioavailability and cancer targeting efficiency of SMAC via their stable nanoparticle-derived EPR effect, leading to effective IAPs inhibition in targeted tumor tissues. "
REF00580	PDC_02072	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	3.9 &plusmn; 0.4 &mu;M	&mu;M	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	"After MHCC-97H cells were treated with Nile blue-stained nanospheres for 4 h, a punctate pattern of red color in the cytoplasm and nucleus was observed, suggesting that R-L-HCPT nanospheres could penetrate cytoplasmic and nuclear membranes to become internalized by MHCC-97H cells."	.	.	.	"In addition, as shown in Table 1, the other cancer cell lines (HeLa, MDA-MB-231, B16-F10, HepG2, and A549) and noncancer cell lines (HEK293t, Beas-2B, and LO2) were evaluated in the cytotoxicity test. The IC50 values of R-L-HCPT were 2.9-6.6 &mu;M for cancer cell lines and 2.8-5.8 &mu;M for noncancer cell lines."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	6.1 &plusmn; 0.1 &mu;M	&mu;M	.	.	.	.	Mouse melanoma	B16-F10 cell	.	.	.	.	.	"In addition, as shown in Table 1, the other cancer cell lines (HeLa, MDA-MB-231, B16-F10, HepG2, and A549) and noncancer cell lines (HEK293t, Beas-2B, and LO2) were evaluated in the cytotoxicity test. The IC50 values of R-L-HCPT were 2.9-6.6 &mu;M for cancer cell lines and 2.8-5.8 &mu;M for noncancer cell lines."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	4.9 &plusmn; 0.3 &mu;M	&mu;M	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	.	.	.	"In addition, as shown in Table 1, the other cancer cell lines (HeLa, MDA-MB-231, B16-F10, HepG2, and A549) and noncancer cell lines (HEK293t, Beas-2B, and LO2) were evaluated in the cytotoxicity test. The IC50 values of R-L-HCPT were 2.9-6.6 &mu;M for cancer cell lines and 2.8-5.8 &mu;M for noncancer cell lines."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	6.6 &plusmn; 0.3 &mu;M	&mu;M	.	.	.	.	Human papillomavirus-related cervical adenocarcinoma	HeLa cell	.	.	.	.	.	"In addition, as shown in Table 1, the other cancer cell lines (HeLa, MDA-MB-231, B16-F10, HepG2, and A549) and noncancer cell lines (HEK293t, Beas-2B, and LO2) were evaluated in the cytotoxicity test. The IC50 values of R-L-HCPT were 2.9-6.6 &mu;M for cancer cell lines and 2.8-5.8 &mu;M for noncancer cell lines."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	2.9 &plusmn; 0.5 &mu;M	&mu;M	.	.	.	.	Hepatoblastoma	Hep-G2 cell	.	.	.	.	.	"In addition, as shown in Table 1, the other cancer cell lines (HeLa, MDA-MB-231, B16-F10, HepG2, and A549) and noncancer cell lines (HEK293t, Beas-2B, and LO2) were evaluated in the cytotoxicity test. The IC50 values of R-L-HCPT were 2.9-6.6 &mu;M for cancer cell lines and 2.8-5.8 &mu;M for noncancer cell lines."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	5.8 &plusmn; 1.1 &mu;M	&mu;M	.	.	.	.	Normal	HEK-293T cell	.	.	.	.	.	"In addition, as shown in Table 1, the other cancer cell lines (HeLa, MDA-MB-231, B16-F10, HepG2, and A549) and noncancer cell lines (HEK293t, Beas-2B, and LO2) were evaluated in the cytotoxicity test. The IC50 values of R-L-HCPT were 2.9-6.6 &mu;M for cancer cell lines and 2.8-5.8 &mu;M for noncancer cell lines."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	4.4 &plusmn; 0.5 &mu;M	&mu;M	.	.	.	.	Normal	BEAS-2B cell	.	.	.	.	.	"In addition, as shown in Table 1, the other cancer cell lines (HeLa, MDA-MB-231, B16-F10, HepG2, and A549) and noncancer cell lines (HEK293t, Beas-2B, and LO2) were evaluated in the cytotoxicity test. The IC50 values of R-L-HCPT were 2.9-6.6 &mu;M for cancer cell lines and 2.8-5.8 &mu;M for noncancer cell lines."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	2.8 &plusmn; 0.4 &mu;M	&mu;M	.	.	.	.	Amelanotic melanoma	LO #2 cell	.	.	.	.	.	"In addition, as shown in Table 1, the other cancer cell lines (HeLa, MDA-MB-231, B16-F10, HepG2, and A549) and noncancer cell lines (HEK293t, Beas-2B, and LO2) were evaluated in the cytotoxicity test. The IC50 values of R-L-HCPT were 2.9-6.6 &mu;M for cancer cell lines and 2.8-5.8 &mu;M for noncancer cell lines."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	3.12 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	MHCC97H cell	.	.	.	.	.	"The IC50 values for R-lycosin-I, R-L-HCPT conjugates, and HCPT were 15.27, 3.12, and 23.83 &mu;M, respectively."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	13.5 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	MHCC97H cell	.	.	6 h	.	.	"The cytotoxic activity of R-L-HCPT on MHCC-97H cells was time-dependent. With R-L-HCPT treatment for 6 and 12 h, the IC50 values were 13.5 &mu;M and 11.7 &mu;M, respectively. However, when the incubation time was extended to 24 and 48 h, the IC50 values were greatly reduced to 3.12 &mu;M and 1.1 &mu;M, respectively."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	11.7 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	MHCC97H cell	.	.	12 h	.	.	"The cytotoxic activity of R-L-HCPT on MHCC-97H cells was time-dependent. With R-L-HCPT treatment for 6 and 12 h, the IC50 values were 13.5 &mu;M and 11.7 &mu;M, respectively. However, when the incubation time was extended to 24 and 48 h, the IC50 values were greatly reduced to 3.12 &mu;M and 1.1 &mu;M, respectively."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	3.12 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	MHCC97H cell	.	.	24 h	.	.	"The cytotoxic activity of R-L-HCPT on MHCC-97H cells was time-dependent. With R-L-HCPT treatment for 6 and 12 h, the IC50 values were 13.5 &mu;M and 11.7 &mu;M, respectively. However, when the incubation time was extended to 24 and 48 h, the IC50 values were greatly reduced to 3.12 &mu;M and 1.1 &mu;M, respectively."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	1.1 &mu;M	&mu;M	.	.	.	.	Hepatocellular carcinoma	MHCC97H cell	.	.	48 h	.	.	"The cytotoxic activity of R-L-HCPT on MHCC-97H cells was time-dependent. With R-L-HCPT treatment for 6 and 12 h, the IC50 values were 13.5 &mu;M and 11.7 &mu;M, respectively. However, when the incubation time was extended to 24 and 48 h, the IC50 values were greatly reduced to 3.12 &mu;M and 1.1 &mu;M, respectively."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	Murine melanoma B16-F10 xenograft model in BALB/c mice.	Discovered Using Cell Line-derived Xenograft Model	.	Body weight	31g	g	.	.	.	.	.	.	.	.	10 days	.	.	"Notably, there were no significant body weight losses (Figure 6D), suggesting that R-L-HCPT did not induce systemic toxicity."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00580	PDC_02072	Solid tumor	Murine melanoma B16-F10 xenograft model in BALB/c mice.	Discovered Using Cell Line-derived Xenograft Model	.	Tumer volume	700 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	10 days	.	.	"Compared with the tumors in the control group with a final tumor volume of 3800 mm<sup>3</sup>, the tumors in the R-L-HCPT group grew much more slowly, and the mean tumor volume expanded from 200 to 700 mm<sup>3</sup> within 10 days."	"Our previous studies demonstrated that R-lycosin-I was a typical cationic anticancer peptide that contained a high relative abundance of positively charged arginine residues and possessed an amphiphilic character to allow its assembly into nanostructures in aqueous environments. Herein, we designed and synthesized a self-assembling anticancer conjugate in which R-lycosin-I covalently coupled with HCPT, a DNA topoisomerase I inhibitor through the glutamic anhydride linker. This conjugate (R-L-HCPT) could spontaneously associate into uniform 40-60 nm nanospheres in aqueous solution. The R-L-HCPT nanospheres exhibited excellent antitumor growth activity and antimetastatic efficacy compared with free HCPT or free R-lycosin-I in vitro and in vivo. Our study might provide new opportunities for the development of a self-assembling peptide-drug delivery system that could synergistically enhance anticancer outcomes."
REF00579	PDC_02073	Solid tumor	GL-261 brain cancer C57BL/6 mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumer volume	0 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	30 days	.	.	"When using the diCPT-iRGD NT hydrogel, the CDA-NT treatment led to substantial tumour regression (Fig. 3c-e) and demonstrated a 100% survival rate in mice (Fig. 3f)."	"In this context, we developed a drug-bearing supramolecular hydrogel system to intratumourally (i.t.) deliver CDNs against malignant tumours to achieve cancer chemoimmunotherapy. Our strategy was to chemically conjugate the hydrophilic pep-tide moiety iRGD (a tumour-penetrating peptide that can bind to neuropilin-1 (NRP-1) and trigger tumour tissue penetration) to the hydrophobic anticancer drug CPT to form a self-assembling and self-formulating peptide-drug conjugate (diCPT-iRGD). In aqueous solution, the designed drug amphiphile spontaneously assembles into supramolecular nanotubes (NTs). The negatively charged STING agonist (c-di-AMP (CDA)) can condense on the surface of these positively charged NTs through electrostatic complexations. After injection into the tumour site, the CDA-NT solution can immediately form a hydrogel, functioning as a local reservoir for extended localized release of CDA and CPT to awaken both the innate and adaptive immune systems."
REF00579	PDC_02073	Solid tumor	GL-261 brain cancer C57BL/6 mice.	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Survival rate	100.00%	%	.	.	.	.	.	.	.	.	30 days	.	.	"When using the diCPT-iRGD NT hydrogel, the CDA-NT treatment led to substantial tumour regression (Fig. 3c-e) and demonstrated a 100% survival rate in mice (Fig. 3f)."	"In this context, we developed a drug-bearing supramolecular hydrogel system to intratumourally (i.t.) deliver CDNs against malignant tumours to achieve cancer chemoimmunotherapy. Our strategy was to chemically conjugate the hydrophilic pep-tide moiety iRGD (a tumour-penetrating peptide that can bind to neuropilin-1 (NRP-1) and trigger tumour tissue penetration) to the hydrophobic anticancer drug CPT to form a self-assembling and self-formulating peptide-drug conjugate (diCPT-iRGD). In aqueous solution, the designed drug amphiphile spontaneously assembles into supramolecular nanotubes (NTs). The negatively charged STING agonist (c-di-AMP (CDA)) can condense on the surface of these positively charged NTs through electrostatic complexations. After injection into the tumour site, the CDA-NT solution can immediately form a hydrogel, functioning as a local reservoir for extended localized release of CDA and CPT to awaken both the innate and adaptive immune systems."
REF00578	PDC_02074	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	98.00%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	.	0.1 &mu;g/ml	MTT assay	"Both the peptide and FPG exhibited no obvious cytotoxicity, while FDPC-NPs and DOX displayed cytotoxicity against tumor cells (IC50 DOX = 2.965 &mu;g/mL; IC50 FDPC-NPs = 5.896 &mu;g/mL) (Figure (Figure6A).6A)."	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00578	PDC_02074	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	85.00%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	.	1 &mu;g/ml	MTT assay	"Both the peptide and FPG exhibited no obvious cytotoxicity, while FDPC-NPs and DOX displayed cytotoxicity against tumor cells (IC50 DOX = 2.965 &mu;g/mL; IC50 FDPC-NPs = 5.896 &mu;g/mL) (Figure (Figure6A).6A)."	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00578	PDC_02074	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	78.00%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	.	2.5 &mu;g/ml	MTT assay	"Both the peptide and FPG exhibited no obvious cytotoxicity, while FDPC-NPs and DOX displayed cytotoxicity against tumor cells (IC50 DOX = 2.965 &mu;g/mL; IC50 FDPC-NPs = 5.896 &mu;g/mL) (Figure (Figure6A).6A)."	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00578	PDC_02074	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	50.00%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	.	5 &mu;g/ml	MTT assay	"Both the peptide and FPG exhibited no obvious cytotoxicity, while FDPC-NPs and DOX displayed cytotoxicity against tumor cells (IC50 DOX = 2.965 &mu;g/mL; IC50 FDPC-NPs = 5.896 &mu;g/mL) (Figure (Figure6A).6A)."	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00578	PDC_02074	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	40.00%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	.	10 &mu;g/ml	MTT assay	"Both the peptide and FPG exhibited no obvious cytotoxicity, while FDPC-NPs and DOX displayed cytotoxicity against tumor cells (IC50 DOX = 2.965 &mu;g/mL; IC50 FDPC-NPs = 5.896 &mu;g/mL) (Figure (Figure6A).6A)."	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00578	PDC_02074	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	25.00%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	.	25 &mu;g/ml	MTT assay	"Both the peptide and FPG exhibited no obvious cytotoxicity, while FDPC-NPs and DOX displayed cytotoxicity against tumor cells (IC50 DOX = 2.965 &mu;g/mL; IC50 FDPC-NPs = 5.896 &mu;g/mL) (Figure (Figure6A).6A)."	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00578	PDC_02074	Solid tumor	.	Revealed Based on the Cell Line Data	.	Cell viability	10.00%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	.	50 &mu;g/ml	MTT assay	"Both the peptide and FPG exhibited no obvious cytotoxicity, while FDPC-NPs and DOX displayed cytotoxicity against tumor cells (IC50 DOX = 2.965 &mu;g/mL; IC50 FDPC-NPs = 5.896 &mu;g/mL) (Figure (Figure6A).6A)."	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00578	PDC_02074	Solid tumor	.	Revealed Based on the Cell Line Data	.	Apotosis rate	22.00%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	.	2 &mu;M	.	"Additionally, the results from flow cytometry with annexin-V-FITC/PI double staining showed that FDPC-NPs and DOX significantly increased the proportion of apoptotic cells in a concentration-dependent manner, and the two groups exhibited similar cytotoxicity. "	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00578	PDC_02074	Solid tumor	.	Revealed Based on the Cell Line Data	.	Apotosis rate	30.00%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	.	10 &mu;M	.	"Additionally, the results from flow cytometry with annexin-V-FITC/PI double staining showed that FDPC-NPs and DOX significantly increased the proportion of apoptotic cells in a concentration-dependent manner, and the two groups exhibited similar cytotoxicity. "	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00578	PDC_02074	Solid tumor	.	Revealed Based on the Cell Line Data	.	Apotosis rate	40.00%	%	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	.	20 &mu;M	.	"Additionally, the results from flow cytometry with annexin-V-FITC/PI double staining showed that FDPC-NPs and DOX significantly increased the proportion of apoptotic cells in a concentration-dependent manner, and the two groups exhibited similar cytotoxicity. "	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00578	PDC_02074	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	5.896 &mu;g/mL	&mu;g/mL	.	.	.	.	Hepatocellular carcinoma	SMMC-7721 cell	.	.	.	.	.	"Both the peptide and FPG exhibited no obvious cytotoxicity, while FDPC-NPs and DOX displayed cytotoxicity against tumor cells (IC50 DOX = 2.965 &mu;g/mL; IC50 FDPC-NPs = 5.896 &mu;g/mL) (Figure (Figure6A).6A)."	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00578	PDC_02074	Solid tumor	H22 hepatocarcinoma tumor-bearing mouse.	Discovered Using Cell Line-derived Xenograft Model	.	Tumer volume	200 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	13 days	10 mg DOX/kg	.	"Results showed that DOX solution, DOX-liposomes and FDPC-NPs displayed significant therapeutic effects against tumors (P < 0.001). Particularly, DOX-liposomes and FDPC-NPs behaved better due to the EPR effect."	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00578	PDC_02074	Solid tumor	H22 hepatocarcinoma tumor-bearing mouse.	Discovered Using Cell Line-derived Xenograft Model	.	Percent survival	95%	%	.	.	.	.	.	.	.	.	13 days	10 mg DOX/kg	.	"Moreover, based on the survivorship curves, treatment with FDPC-NPs remarkably promoted the survival rate of tumor-bearing mice, which furtherly confirmed the therapeutic effect and biological safety of FDPC-NPs."	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00578	PDC_02074	Solid tumor	H22 hepatocarcinoma tumor-bearing mouse.	Discovered Using Cell Line-derived Xenograft Model	.	Body weight	32g	g	.	.	.	.	.	.	.	.	13 days	10 mg DOX/kg	.	"On the contrary, the administration of DOX-liposomes and FDPC-NPs barely influenced the body weights of the model mice, revealing the safety of DOX-liposomes and FDPC-NPs. "	"In this work, we reported doxorubicin-peptide conjugates (DPCs) with an extracellular tumor acid-responsive sphere-fiber transformation for enhanced residence in tumors. As illustrated in Scheme Scheme1,1, the chemotherapy drug doxorubicin (DOX) was coupled with a peptide (KIGLFRWR) to design a DPC molecule with assembly ability. First, the DPCs, driven by hydrophobic forces from the hydrophobic drug DOX and the IGL fragment, can form spherical DPC nanoparticles (DPC-NPs). Then, along with hydrogen bond between peptides, the aromatic amino acids F and W give the DPC-NPs the ability of self-assembly to DPC-nanofibers (DPC-NFs) due to &pi;-&pi; stacking. The step-by-step assembly process provides opportunities for morphological transformation control. To meet the particle size requirements for intravenous injection, the acid-responsive material 2,3-dimethylmaleic anhydride grafted polylysine, named the functional polylysine graft (FPG), was designed as a shielding layer for DPC-NPs and formed functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) by an electrostatic interaction to avoid &pi;-&pi; stacking interactions and hydrogen bond between the DPC-NPs. Therefore, the FDPC-NPs could maintain an appropriate size in blood vessels until entering the tumor stroma by the EPR effect. When the FDPC-NPs passed through the blood vessel and entered the weakly acidic microenvironment of the tumor, the surface potential of the shield was reversed from negative to positive because of acid-sensitive 2,3-dimethylmaleic groups on the FPG. Therefore, FPG would separate from the DPC-NPs because of the mutual repulsion effect from the like charges. Then, DPC-NPs self-assembled into DPC-NFs, thereby staying in the tumor region for a long time. After that, the fibers degraded gradually and free drug penetrated into tumor cells, exerting sustained anti-tumor effect. This study is original and provides new ideas for the design of targeted and long-acting drug delivery systems for tumor therapy."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	101%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.1 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	100%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.5 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	65%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	1.0 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	100%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	10 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	75%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	50 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	50%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	75 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	40%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	100 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	55%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.1 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	75%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.5 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	35%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	1.0 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	25%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	10 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	30%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	50 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	25%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	75 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	20%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	100 &mu;M	.	"D492HER2 cells showed increased sensitivity to melphalan compared to the progenitor cell line D492. However, concentration as high as 100 &mu;mol/L was insufficient to kill the whole cell population. In both cell lines, around 40% of D492 cells and at least 20% of D492HER2 cells were still viable after incubation with 100 &mu;mol/L melphalan. On the contrary, melflufen decreased viability of both D492 and D492HER2 cells at much lower doses. "	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	80%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.1 &mu;M	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	84%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.5 &mu;M	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	95%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.7 &mu;M	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	70%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	1.0 &mu;M	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	48%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	1.5 &mu;M	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	25%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	2.0 &mu;M	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	86%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.1 &mu;M; with bestatin (10 &mu;mol/L)	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	82%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.5 &mu;M; with bestatin (10 &mu;mol/L)	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	60%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.7 &mu;M; with bestatin (10 &mu;mol/L)	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	50%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	1.0 &mu;M; with bestatin (10 &mu;mol/L)	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	30%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	1.5 &mu;M; with bestatin (10 &mu;mol/L)	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	22%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	2.0 &mu;M; with bestatin (10 &mu;mol/L)	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	98%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.1 &mu;M	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	70%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.5 &mu;M	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	65%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.7 &mu;M	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	55%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	1.0 &mu;M	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	30%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	1.5 &mu;M	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	25%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	2.0 &mu;M	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	99%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.1 &mu;M; with bestatin (10 &mu;mol/L)	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	120%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.5 &mu;M; with bestatin (10 &mu;mol/L)	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	97%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	0.7 &mu;M; with bestatin (10 &mu;mol/L)	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	90%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	1.0 &mu;M; with bestatin (10 &mu;mol/L)	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	80%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	1.5 &mu;M; with bestatin (10 &mu;mol/L)	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	45%	%	.	.	.	.	Normal	D492 cell	.	.	48 h	2.0 &mu;M; with bestatin (10 &mu;mol/L)	.	"Aminopeptidases are thought to be responsible for the cleavage of melflufen, and indeed, in our model, the aminopeptidase inhibitor bestatin attenuated the activity of melflufen in D492HER2 cells. Interestingly, in D492 cells, preincubation with bestatin showed no effect on melflufen activity."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	75%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	0.1 &mu;M	.	"While these cells tolerated higher drug concentrations for both drugs compared to our D492 cell lines, melflufen was significantly more efficient than doxorubicin in killing the MDAMB231 cells (Figure 3C)."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	74%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	0.5 &mu;M	.	"While these cells tolerated higher drug concentrations for both drugs compared to our D492 cell lines, melflufen was significantly more efficient than doxorubicin in killing the MDAMB231 cells (Figure 3C)."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	73%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	1 &mu;M	.	"While these cells tolerated higher drug concentrations for both drugs compared to our D492 cell lines, melflufen was significantly more efficient than doxorubicin in killing the MDAMB231 cells (Figure 3C)."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	40%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	2 &mu;M	.	"While these cells tolerated higher drug concentrations for both drugs compared to our D492 cell lines, melflufen was significantly more efficient than doxorubicin in killing the MDAMB231 cells (Figure 3C)."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	25%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	5 &mu;M	.	"While these cells tolerated higher drug concentrations for both drugs compared to our D492 cell lines, melflufen was significantly more efficient than doxorubicin in killing the MDAMB231 cells (Figure 3C)."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	20%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	48 h	10 &mu;M	.	"While these cells tolerated higher drug concentrations for both drugs compared to our D492 cell lines, melflufen was significantly more efficient than doxorubicin in killing the MDAMB231 cells (Figure 3C)."	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	0.046 &mu;mol/L	&mu;mol/L	.	.	.	.	Normal	D492 cell	.	.	.	.	.	IC50 values for melflufen of 0.046 &mu;mol/L in D492HER2 cells and 0.52 &mu;mol/L in D492 cells compared to doxorubicin values of 0.92 &mu;mol/L for D492HER2 cells and 1.8 &mu;mol/L for D492 underpin these findings (Figure 3B).	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00577	PDC_00239	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	0.52 &mu;mol/L	&mu;mol/L	.	.	.	.	Normal	D492 cell	.	.	.	.	.	IC50 values for melflufen of 0.046 &mu;mol/L in D492HER2 cells and 0.52 &mu;mol/L in D492 cells compared to doxorubicin values of 0.92 &mu;mol/L for D492HER2 cells and 1.8 &mu;mol/L for D492 underpin these findings (Figure 4B).	"Melphalan is a wellknown cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptideconjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily. Inside the cell, melflufen is rapidly hydrolyzed into less lipophilic metabolites that retain high alkylating potential, leading to their entrapment and accumulation. Aminopeptidases belong to a large family of enzymes that catalyze the cleavage of amino acids from the amino terminus of proteins or peptides and are shown to facilitate intracellular hydrolysis of melflufen. Aminopeptidases are involved in multiple cellular processes, and their expression and activity are frequently deregulated in cancer cells. For this reason, aminopeptidase inhibitors bestatin and tosedostat have been investigated in the clinical settings. Exploiting aminopeptidase activity to convert a lipophilic drug such as melflufen to an intracellular hydrophilic metabolite with high alkylating potential may offer an effective alternative therapeutic approach. Previously it has been shown that aminopeptidase N (ANPEP or CD13) can hydrolyze melflufen, but it is largely unknown whether melflufen can be a substrate for other aminopeptidases. Application of melflufen has mainly been focused on multiple myeloma, where it has shown promising results in phase 3 clinical trial in relapse and refractory patient population. 13 Yet it is unexplored whether melflufen can be effective in other cancer types such as breast cancer. Here, we demonstrate the efficacy of melflufen in D492HER2 breast epithelial cells overexpressing the HER2 oncogene and the triplenegative cell line MDAMB231."
REF00570	PDC_02085	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	5.00%	%	.	.	.	.	Colon adenocarcinoma	HT-29 cell	.	.	6 days	0.03 mM	.	"This clearly indicated that the chemotherapeutic moiety was released into the cell medium and the drug was internalized into the cells, probably by membrane diffusion. This became evident when observing the behavior of the unrelated conjugated peptides."	"We have been studying protease-resistant branched peptides as tumor targeting agents by using tetra-branched peptides (NT4) containing the human regulatory peptide neurotensin (NT) sequence. Neurotensin receptors are overexpressed in several human malignancies, such as colon, pancreatic, prostate and small-cell lung cancer. We have been using NT4 conjugated to different functional units for tumor imaging and therapy, and found that NT4 conjugated to methotrexate produced 60% reduction of tumor growth in xenografted mice. Results obtained with NT4 indicated that branched peptides are promising novel multifunctional targeting molecules, which might allow cancer detection and therapy by means of the same molecule, with no modification in target binding, but rather a simple exchange of functional units. Since cancer cells are very different from one another in terms of drug sensibility, not only in different tumors but in different patients and stages of the disease, this approach prefigures the synthesis of a number of constructs conjugated with differently acting chemotherapeutics. The type of linkage between effector unit (drug/imaging agent etc.) and peptide is obviously crucial for this type of approach. The choice must be driven by two issues: 1) The nature of the drug functional groups available for coupling with the peptide; and 2) the mechanism-of-action of the drug. When a prodrug acts without being released from the carrier unit, a strong linker is preferred. However, if a drug has to be released in order to interact with the intracellular target, the linker must be cleavable. In latter, the linker has to be chosen properly-not too labile or leakage will occur during drug distribution, but not too robust or the pharmacological action will be impaired."
REF00570	PDC_02085	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	50.00%	%	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	6 days	0.03 mM	.	"This clearly indicated that the chemotherapeutic moiety was released into the cell medium and the drug was internalized into the cells, probably by membrane diffusion. This became evident when observing the behavior of the unrelated conjugated peptides."	"We have been studying protease-resistant branched peptides as tumor targeting agents by using tetra-branched peptides (NT4) containing the human regulatory peptide neurotensin (NT) sequence. Neurotensin receptors are overexpressed in several human malignancies, such as colon, pancreatic, prostate and small-cell lung cancer. We have been using NT4 conjugated to different functional units for tumor imaging and therapy, and found that NT4 conjugated to methotrexate produced 60% reduction of tumor growth in xenografted mice. Results obtained with NT4 indicated that branched peptides are promising novel multifunctional targeting molecules, which might allow cancer detection and therapy by means of the same molecule, with no modification in target binding, but rather a simple exchange of functional units. Since cancer cells are very different from one another in terms of drug sensibility, not only in different tumors but in different patients and stages of the disease, this approach prefigures the synthesis of a number of constructs conjugated with differently acting chemotherapeutics. The type of linkage between effector unit (drug/imaging agent etc.) and peptide is obviously crucial for this type of approach. The choice must be driven by two issues: 1) The nature of the drug functional groups available for coupling with the peptide; and 2) the mechanism-of-action of the drug. When a prodrug acts without being released from the carrier unit, a strong linker is preferred. However, if a drug has to be released in order to interact with the intracellular target, the linker must be cleavable. In latter, the linker has to be chosen properly-not too labile or leakage will occur during drug distribution, but not too robust or the pharmacological action will be impaired."
REF00570	PDC_02085	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	0.00%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	6 days	0.03 mM	.	"This clearly indicated that the chemotherapeutic moiety was released into the cell medium and the drug was internalized into the cells, probably by membrane diffusion. This became evident when observing the behavior of the unrelated conjugated peptides."	"We have been studying protease-resistant branched peptides as tumor targeting agents by using tetra-branched peptides (NT4) containing the human regulatory peptide neurotensin (NT) sequence. Neurotensin receptors are overexpressed in several human malignancies, such as colon, pancreatic, prostate and small-cell lung cancer. We have been using NT4 conjugated to different functional units for tumor imaging and therapy, and found that NT4 conjugated to methotrexate produced 60% reduction of tumor growth in xenografted mice. Results obtained with NT4 indicated that branched peptides are promising novel multifunctional targeting molecules, which might allow cancer detection and therapy by means of the same molecule, with no modification in target binding, but rather a simple exchange of functional units. Since cancer cells are very different from one another in terms of drug sensibility, not only in different tumors but in different patients and stages of the disease, this approach prefigures the synthesis of a number of constructs conjugated with differently acting chemotherapeutics. The type of linkage between effector unit (drug/imaging agent etc.) and peptide is obviously crucial for this type of approach. The choice must be driven by two issues: 1) The nature of the drug functional groups available for coupling with the peptide; and 2) the mechanism-of-action of the drug. When a prodrug acts without being released from the carrier unit, a strong linker is preferred. However, if a drug has to be released in order to interact with the intracellular target, the linker must be cleavable. In latter, the linker has to be chosen properly-not too labile or leakage will occur during drug distribution, but not too robust or the pharmacological action will be impaired."
REF00570	PDC_02086	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	100.00%	%	.	.	.	.	Colon adenocarcinoma	HT-29 cell	.	.	6 days	0.03 mM	.	"This clearly indicated that the chemotherapeutic moiety was released into the cell medium and the drug was internalized into the cells, probably by membrane diffusion. This became evident when observing the behavior of the unrelated conjugated peptides."	"We have been studying protease-resistant branched peptides as tumor targeting agents by using tetra-branched peptides (NT4) containing the human regulatory peptide neurotensin (NT) sequence. Neurotensin receptors are overexpressed in several human malignancies, such as colon, pancreatic, prostate and small-cell lung cancer. We have been using NT4 conjugated to different functional units for tumor imaging and therapy, and found that NT4 conjugated to methotrexate produced 60% reduction of tumor growth in xenografted mice. Results obtained with NT4 indicated that branched peptides are promising novel multifunctional targeting molecules, which might allow cancer detection and therapy by means of the same molecule, with no modification in target binding, but rather a simple exchange of functional units. Since cancer cells are very different from one another in terms of drug sensibility, not only in different tumors but in different patients and stages of the disease, this approach prefigures the synthesis of a number of constructs conjugated with differently acting chemotherapeutics. The type of linkage between effector unit (drug/imaging agent etc.) and peptide is obviously crucial for this type of approach. The choice must be driven by two issues: 1) The nature of the drug functional groups available for coupling with the peptide; and 2) the mechanism-of-action of the drug. When a prodrug acts without being released from the carrier unit, a strong linker is preferred. However, if a drug has to be released in order to interact with the intracellular target, the linker must be cleavable. In latter, the linker has to be chosen properly-not too labile or leakage will occur during drug distribution, but not too robust or the pharmacological action will be impaired."
REF00570	PDC_02086	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	0.00%	%	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	6 days	0.03 mM	.	"This clearly indicated that the chemotherapeutic moiety was released into the cell medium and the drug was internalized into the cells, probably by membrane diffusion. This became evident when observing the behavior of the unrelated conjugated peptides."	"We have been studying protease-resistant branched peptides as tumor targeting agents by using tetra-branched peptides (NT4) containing the human regulatory peptide neurotensin (NT) sequence. Neurotensin receptors are overexpressed in several human malignancies, such as colon, pancreatic, prostate and small-cell lung cancer. We have been using NT4 conjugated to different functional units for tumor imaging and therapy, and found that NT4 conjugated to methotrexate produced 60% reduction of tumor growth in xenografted mice. Results obtained with NT4 indicated that branched peptides are promising novel multifunctional targeting molecules, which might allow cancer detection and therapy by means of the same molecule, with no modification in target binding, but rather a simple exchange of functional units. Since cancer cells are very different from one another in terms of drug sensibility, not only in different tumors but in different patients and stages of the disease, this approach prefigures the synthesis of a number of constructs conjugated with differently acting chemotherapeutics. The type of linkage between effector unit (drug/imaging agent etc.) and peptide is obviously crucial for this type of approach. The choice must be driven by two issues: 1) The nature of the drug functional groups available for coupling with the peptide; and 2) the mechanism-of-action of the drug. When a prodrug acts without being released from the carrier unit, a strong linker is preferred. However, if a drug has to be released in order to interact with the intracellular target, the linker must be cleavable. In latter, the linker has to be chosen properly-not too labile or leakage will occur during drug distribution, but not too robust or the pharmacological action will be impaired."
REF00570	PDC_02086	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	20.00%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	6 days	0.03 mM	.	"This clearly indicated that the chemotherapeutic moiety was released into the cell medium and the drug was internalized into the cells, probably by membrane diffusion. This became evident when observing the behavior of the unrelated conjugated peptides."	"We have been studying protease-resistant branched peptides as tumor targeting agents by using tetra-branched peptides (NT4) containing the human regulatory peptide neurotensin (NT) sequence. Neurotensin receptors are overexpressed in several human malignancies, such as colon, pancreatic, prostate and small-cell lung cancer. We have been using NT4 conjugated to different functional units for tumor imaging and therapy, and found that NT4 conjugated to methotrexate produced 60% reduction of tumor growth in xenografted mice. Results obtained with NT4 indicated that branched peptides are promising novel multifunctional targeting molecules, which might allow cancer detection and therapy by means of the same molecule, with no modification in target binding, but rather a simple exchange of functional units. Since cancer cells are very different from one another in terms of drug sensibility, not only in different tumors but in different patients and stages of the disease, this approach prefigures the synthesis of a number of constructs conjugated with differently acting chemotherapeutics. The type of linkage between effector unit (drug/imaging agent etc.) and peptide is obviously crucial for this type of approach. The choice must be driven by two issues: 1) The nature of the drug functional groups available for coupling with the peptide; and 2) the mechanism-of-action of the drug. When a prodrug acts without being released from the carrier unit, a strong linker is preferred. However, if a drug has to be released in order to interact with the intracellular target, the linker must be cleavable. In latter, the linker has to be chosen properly-not too labile or leakage will occur during drug distribution, but not too robust or the pharmacological action will be impaired."
REF00570	PDC_02087	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	0.00%	%	.	.	.	.	Colon adenocarcinoma	HT-29 cell	.	.	6 days	0.03 mM	.	"This clearly indicated that the chemotherapeutic moiety was released into the cell medium and the drug was internalized into the cells, probably by membrane diffusion. This became evident when observing the behavior of the unrelated conjugated peptides."	"We have been studying protease-resistant branched peptides as tumor targeting agents by using tetra-branched peptides (NT4) containing the human regulatory peptide neurotensin (NT) sequence. Neurotensin receptors are overexpressed in several human malignancies, such as colon, pancreatic, prostate and small-cell lung cancer. We have been using NT4 conjugated to different functional units for tumor imaging and therapy, and found that NT4 conjugated to methotrexate produced 60% reduction of tumor growth in xenografted mice. Results obtained with NT4 indicated that branched peptides are promising novel multifunctional targeting molecules, which might allow cancer detection and therapy by means of the same molecule, with no modification in target binding, but rather a simple exchange of functional units. Since cancer cells are very different from one another in terms of drug sensibility, not only in different tumors but in different patients and stages of the disease, this approach prefigures the synthesis of a number of constructs conjugated with differently acting chemotherapeutics. The type of linkage between effector unit (drug/imaging agent etc.) and peptide is obviously crucial for this type of approach. The choice must be driven by two issues: 1) The nature of the drug functional groups available for coupling with the peptide; and 2) the mechanism-of-action of the drug. When a prodrug acts without being released from the carrier unit, a strong linker is preferred. However, if a drug has to be released in order to interact with the intracellular target, the linker must be cleavable. In latter, the linker has to be chosen properly-not too labile or leakage will occur during drug distribution, but not too robust or the pharmacological action will be impaired."
REF00570	PDC_02087	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	55.00%	%	.	.	.	.	Pancreatic ductal adenocarcinoma	PANC-1 cell	.	.	6 days	0.03 mM	.	"This clearly indicated that the chemotherapeutic moiety was released into the cell medium and the drug was internalized into the cells, probably by membrane diffusion. This became evident when observing the behavior of the unrelated conjugated peptides."	"We have been studying protease-resistant branched peptides as tumor targeting agents by using tetra-branched peptides (NT4) containing the human regulatory peptide neurotensin (NT) sequence. Neurotensin receptors are overexpressed in several human malignancies, such as colon, pancreatic, prostate and small-cell lung cancer. We have been using NT4 conjugated to different functional units for tumor imaging and therapy, and found that NT4 conjugated to methotrexate produced 60% reduction of tumor growth in xenografted mice. Results obtained with NT4 indicated that branched peptides are promising novel multifunctional targeting molecules, which might allow cancer detection and therapy by means of the same molecule, with no modification in target binding, but rather a simple exchange of functional units. Since cancer cells are very different from one another in terms of drug sensibility, not only in different tumors but in different patients and stages of the disease, this approach prefigures the synthesis of a number of constructs conjugated with differently acting chemotherapeutics. The type of linkage between effector unit (drug/imaging agent etc.) and peptide is obviously crucial for this type of approach. The choice must be driven by two issues: 1) The nature of the drug functional groups available for coupling with the peptide; and 2) the mechanism-of-action of the drug. When a prodrug acts without being released from the carrier unit, a strong linker is preferred. However, if a drug has to be released in order to interact with the intracellular target, the linker must be cleavable. In latter, the linker has to be chosen properly-not too labile or leakage will occur during drug distribution, but not too robust or the pharmacological action will be impaired."
REF00570	PDC_02087	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	0.00%	%	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	6 days	0.03 mM	.	"This clearly indicated that the chemotherapeutic moiety was released into the cell medium and the drug was internalized into the cells, probably by membrane diffusion. This became evident when observing the behavior of the unrelated conjugated peptides."	"We have been studying protease-resistant branched peptides as tumor targeting agents by using tetra-branched peptides (NT4) containing the human regulatory peptide neurotensin (NT) sequence. Neurotensin receptors are overexpressed in several human malignancies, such as colon, pancreatic, prostate and small-cell lung cancer. We have been using NT4 conjugated to different functional units for tumor imaging and therapy, and found that NT4 conjugated to methotrexate produced 60% reduction of tumor growth in xenografted mice. Results obtained with NT4 indicated that branched peptides are promising novel multifunctional targeting molecules, which might allow cancer detection and therapy by means of the same molecule, with no modification in target binding, but rather a simple exchange of functional units. Since cancer cells are very different from one another in terms of drug sensibility, not only in different tumors but in different patients and stages of the disease, this approach prefigures the synthesis of a number of constructs conjugated with differently acting chemotherapeutics. The type of linkage between effector unit (drug/imaging agent etc.) and peptide is obviously crucial for this type of approach. The choice must be driven by two issues: 1) The nature of the drug functional groups available for coupling with the peptide; and 2) the mechanism-of-action of the drug. When a prodrug acts without being released from the carrier unit, a strong linker is preferred. However, if a drug has to be released in order to interact with the intracellular target, the linker must be cleavable. In latter, the linker has to be chosen properly-not too labile or leakage will occur during drug distribution, but not too robust or the pharmacological action will be impaired."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	6 &mu;M	&mu;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	29 &mu;M	&mu;M	.	.	.	.	Breast cancer	MCF-7/6 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	133 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7/ADR cell	.	.	Three injections per week for 3 weeks	.	.	"These experiments showed that it is possible to overcome the doxorubicin-resistant phenotype by conjugation of doxorubicin to Vectocell peptides. Vectocell peptides DPV1047 (8a and 12a) and DPV10 (8b and 9b) are able to inhibit the doxorubicin- resistant phenotype of MCF7-Adr cells. However, the compounds 8a and 9b exhibited the greatest cytotoxic activity in the doxorubicin-resistant cell model, although 9b showed a loss of cytotoxic activity in the HCT116 in vitro model (Table 1). The in vitro data therefore suggested that the optimal conjugate for both doxorubicin-sensitive and -resistant models was 8a."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Relative tumor volume	29.50%	%	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The conjugates 8a-c all showed activity; the most active was 8a. Compound 12a showed no activity and confirmed the in vitro data. In a second experiment, conjugates 9c, 9b, and 8a were compared. Compound 9c was completely inactive and 9b was only partially active, which correlated with the reduction of in vitro cytotoxicity of both 9c and 9b compared to 8a observed in the HCT116 model. The in vivo evaluation of the Vectocell-doxorubicin conjugates confirmed that 8a (15 &mu;mol/kg) is the optimal conjugate with a T/C value of 29.5% (Table 1), whereas T/C obtained with the other conjugates ranged from 34.1% (8c) to 86.2% (9c). Moreover, in this experiment, the conjugate 8a (15 &mu;mol/kg) showed better efficacy than doxorubicin (10, 6.5 &mu;mol/kg: doxorubucin's maximal tolerated dose, MTD), with a T/C of 49.6%. It should be noted that it is possible to administer 8a at twice the MTD of doxorubicin (10), demonstrating that 8a is less toxic and more active than 10. For this reason 8a was therefore selected for further preclinical evaluation in both doxorubicin-sensitive and -resistant models."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Colon adenocarcinoma	HCT 15 cell	.	.	.	.	.	"In these resistant cell lines, DPV1047-E-Dox (8a) always showed better antiproliferative activity than doxorubicin. In MCF7-Adr and MES-SA-dx5 cells, which express high levels of Pgp, the enhanced efficacy of DPV1047-E-Dox (8a) was highly significant compared to that of doxorubicin alone (p < 0.001)."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	81 &mu;M	&mu;M	.	.	.	.	Uterine sarcoma	MES-SA/Dx5 cell	.	.	.	.	.	"In these resistant cell lines, DPV1047-E-Dox (8a) always showed better antiproliferative activity than doxorubicin. In MCF7-Adr and MES-SA-dx5 cells, which express high levels of Pgp, the enhanced efficacy of DPV1047-E-Dox (8a) was highly significant compared to that of doxorubicin alone (p < 0.001)."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	260 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7/ADR cell	.	.	.	.	.	"In these resistant cell lines, DPV1047-E-Dox (8a) always showed better antiproliferative activity than doxorubicin. In MCF7-Adr and MES-SA-dx5 cells, which express high levels of Pgp, the enhanced efficacy of DPV1047-E-Dox (8a) was highly significant compared to that of doxorubicin alone (p < 0.001)."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	5 &mu;M	&mu;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	.	.	.	"In the case of Vp followed by DPV1047-E-Dox (8a) treatment, only a moderate increase in sensitivity was observed, with only a 3.6-5-fold increase in activity. The difference between doxorubicin (10) and DPV1047-E-Dox (8a) cytotoxicity following Vp treatment suggests that DPV1047-E-Dox (8a) is a poor substrate for Pgp-mediated cell extrusion, which could result in an increase in the intracellular concentration of the therapeutic molecule."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	50 &mu;M	&mu;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	.	.	.	"In the case of Vp followed by DPV1047-E-Dox (8a) treatment, only a moderate increase in sensitivity was observed, with only a 3.6-5-fold increase in activity. The difference between doxorubicin (10) and DPV1047-E-Dox (8a) cytotoxicity following Vp treatment suggests that DPV1047-E-Dox (8a) is a poor substrate for Pgp-mediated cell extrusion, which could result in an increase in the intracellular concentration of the therapeutic molecule."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	260 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7/ADR cell	.	.	.	.	.	"In the case of Vp followed by DPV1047-E-Dox (8a) treatment, only a moderate increase in sensitivity was observed, with only a 3.6-5-fold increase in activity. The difference between doxorubicin (10) and DPV1047-E-Dox (8a) cytotoxicity following Vp treatment suggests that DPV1047-E-Dox (8a) is a poor substrate for Pgp-mediated cell extrusion, which could result in an increase in the intracellular concentration of the therapeutic molecule."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	79 &mu;M	&mu;M	.	.	.	.	Uterine sarcoma	MES-SA/Dx5 cell	.	.	.	.	.	"In the case of Vp followed by DPV1047-E-Dox (8a) treatment, only a moderate increase in sensitivity was observed, with only a 3.6-5-fold increase in activity. The difference between doxorubicin (10) and DPV1047-E-Dox (8a) cytotoxicity following Vp treatment suggests that DPV1047-E-Dox (8a) is a poor substrate for Pgp-mediated cell extrusion, which could result in an increase in the intracellular concentration of the therapeutic molecule."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	4 &mu;M	&mu;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	.	.	.	"In the case of Vp followed by DPV1047-E-Dox (8a) treatment, only a moderate increase in sensitivity was observed, with only a 3.6-5-fold increase in activity. The difference between doxorubicin (10) and DPV1047-E-Dox (8a) cytotoxicity following Vp treatment suggests that DPV1047-E-Dox (8a) is a poor substrate for Pgp-mediated cell extrusion, which could result in an increase in the intracellular concentration of the therapeutic molecule."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	11 &mu;M	&mu;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	.	.	.	"In the case of Vp followed by DPV1047-E-Dox (8a) treatment, only a moderate increase in sensitivity was observed, with only a 3.6-5-fold increase in activity. The difference between doxorubicin (10) and DPV1047-E-Dox (8a) cytotoxicity following Vp treatment suggests that DPV1047-E-Dox (8a) is a poor substrate for Pgp-mediated cell extrusion, which could result in an increase in the intracellular concentration of the therapeutic molecule."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	52 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7/ADR cell	.	.	.	.	.	"In the case of Vp followed by DPV1047-E-Dox (8a) treatment, only a moderate increase in sensitivity was observed, with only a 3.6-5-fold increase in activity. The difference between doxorubicin (10) and DPV1047-E-Dox (8a) cytotoxicity following Vp treatment suggests that DPV1047-E-Dox (8a) is a poor substrate for Pgp-mediated cell extrusion, which could result in an increase in the intracellular concentration of the therapeutic molecule."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02075	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	22 &mu;M	&mu;M	.	.	.	.	Uterine sarcoma	MES-SA/Dx5 cell	.	.	.	.	.	"In the case of Vp followed by DPV1047-E-Dox (8a) treatment, only a moderate increase in sensitivity was observed, with only a 3.6-5-fold increase in activity. The difference between doxorubicin (10) and DPV1047-E-Dox (8a) cytotoxicity following Vp treatment suggests that DPV1047-E-Dox (8a) is a poor substrate for Pgp-mediated cell extrusion, which could result in an increase in the intracellular concentration of the therapeutic molecule."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02076	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	2 &mu;M	&mu;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02076	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	9 &mu;M	&mu;M	.	.	.	.	Breast cancer	MCF-7/6 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02076	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	532 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7/ADR cell	.	.	Three injections per week for 3 weeks	.	.	"These experiments showed that it is possible to overcome the doxorubicin-resistant phenotype by conjugation of doxorubicin to Vectocell peptides. Vectocell peptides DPV1047 (8a and 12a) and DPV10 (8b and 9b) are able to inhibit the doxorubicin- resistant phenotype of MCF7-Adr cells. However, the compounds 8a and 9b exhibited the greatest cytotoxic activity in the doxorubicin-resistant cell model, although 9b showed a loss of cytotoxic activity in the HCT116 in vitro model (Table 1). The in vitro data therefore suggested that the optimal conjugate for both doxorubicin-sensitive and -resistant models was 8a."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02076	Solid tumor	.	Revealed Based on the Cell Line Data	.	Relative tumor volume	39%	%	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The conjugates 8a-c all showed activity; the most active was 8a. Compound 12a showed no activity and confirmed the in vitro data. In a second experiment, conjugates 9c, 9b, and 8a were compared. Compound 9c was completely inactive and 9b was only partially active, which correlated with the reduction of in vitro cytotoxicity of both 9c and 9b compared to 8a observed in the HCT116 model. The in vivo evaluation of the Vectocell-doxorubicin conjugates confirmed that 8a (15 &mu;mol/kg) is the optimal conjugate with a T/C value of 29.5% (Table 1), whereas T/C obtained with the other conjugates ranged from 34.1% (8c) to 86.2% (9c). Moreover, in this experiment, the conjugate 8a (15 &mu;mol/kg) showed better efficacy than doxorubicin (10, 6.5 &mu;mol/kg: doxorubucin's maximal tolerated dose, MTD), with a T/C of 49.6%. It should be noted that it is possible to administer 8a at twice the MTD of doxorubicin (10), demonstrating that 8a is less toxic and more active than 10. For this reason 8a was therefore selected for further preclinical evaluation in both doxorubicin-sensitive and -resistant models."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02077	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	5 &mu;M	&mu;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02077	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	10 &mu;M	&mu;M	.	.	.	.	Breast cancer	MCF-7/6 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02077	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	 1000 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7/ADR cell	.	.	Three injections per week for 3 weeks	.	.	"These experiments showed that it is possible to overcome the doxorubicin-resistant phenotype by conjugation of doxorubicin to Vectocell peptides. Vectocell peptides DPV1047 (8a and 12a) and DPV10 (8b and 9b) are able to inhibit the doxorubicin- resistant phenotype of MCF7-Adr cells. However, the compounds 8a and 9b exhibited the greatest cytotoxic activity in the doxorubicin-resistant cell model, although 9b showed a loss of cytotoxic activity in the HCT116 in vitro model (Table 1). The in vitro data therefore suggested that the optimal conjugate for both doxorubicin-sensitive and -resistant models was 8a."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02077	Solid tumor	.	Revealed Based on the Cell Line Data	.	Relative tumor volume	34.10%	%	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The conjugates 8a-c all showed activity; the most active was 8a. Compound 12a showed no activity and confirmed the in vitro data. In a second experiment, conjugates 9c, 9b, and 8a were compared. Compound 9c was completely inactive and 9b was only partially active, which correlated with the reduction of in vitro cytotoxicity of both 9c and 9b compared to 8a observed in the HCT116 model. The in vivo evaluation of the Vectocell-doxorubicin conjugates confirmed that 8a (15 &mu;mol/kg) is the optimal conjugate with a T/C value of 29.5% (Table 1), whereas T/C obtained with the other conjugates ranged from 34.1% (8c) to 86.2% (9c). Moreover, in this experiment, the conjugate 8a (15 &mu;mol/kg) showed better efficacy than doxorubicin (10, 6.5 &mu;mol/kg: doxorubucin's maximal tolerated dose, MTD), with a T/C of 49.6%. It should be noted that it is possible to administer 8a at twice the MTD of doxorubicin (10), demonstrating that 8a is less toxic and more active than 10. For this reason 8a was therefore selected for further preclinical evaluation in both doxorubicin-sensitive and -resistant models."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02078	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	153 &mu;M	&mu;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02078	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	37 &mu;M	&mu;M	.	.	.	.	Breast cancer	MCF-7/6 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02078	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	121 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7/ADR cell	.	.	Three injections per week for 3 weeks	.	.	"These experiments showed that it is possible to overcome the doxorubicin-resistant phenotype by conjugation of doxorubicin to Vectocell peptides. Vectocell peptides DPV1047 (8a and 12a) and DPV10 (8b and 9b) are able to inhibit the doxorubicin- resistant phenotype of MCF7-Adr cells. However, the compounds 8a and 9b exhibited the greatest cytotoxic activity in the doxorubicin-resistant cell model, although 9b showed a loss of cytotoxic activity in the HCT116 in vitro model (Table 1). The in vitro data therefore suggested that the optimal conjugate for both doxorubicin-sensitive and -resistant models was 8a."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02078	Solid tumor	.	Revealed Based on the Cell Line Data	.	Relative tumor volume	55.80%	%	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The conjugates 8a-c all showed activity; the most active was 8a. Compound 12a showed no activity and confirmed the in vitro data. In a second experiment, conjugates 9c, 9b, and 8a were compared. Compound 9c was completely inactive and 9b was only partially active, which correlated with the reduction of in vitro cytotoxicity of both 9c and 9b compared to 8a observed in the HCT116 model. The in vivo evaluation of the Vectocell-doxorubicin conjugates confirmed that 8a (15 &mu;mol/kg) is the optimal conjugate with a T/C value of 29.5% (Table 1), whereas T/C obtained with the other conjugates ranged from 34.1% (8c) to 86.2% (9c). Moreover, in this experiment, the conjugate 8a (15 &mu;mol/kg) showed better efficacy than doxorubicin (10, 6.5 &mu;mol/kg: doxorubucin's maximal tolerated dose, MTD), with a T/C of 49.6%. It should be noted that it is possible to administer 8a at twice the MTD of doxorubicin (10), demonstrating that 8a is less toxic and more active than 10. For this reason 8a was therefore selected for further preclinical evaluation in both doxorubicin-sensitive and -resistant models."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02079	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	30 &mu;M	&mu;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02079	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	17 &mu;M	&mu;M	.	.	.	.	Breast cancer	MCF-7/6 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02079	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	862 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7/ADR cell	.	.	Three injections per week for 3 weeks	.	.	"These experiments showed that it is possible to overcome the doxorubicin-resistant phenotype by conjugation of doxorubicin to Vectocell peptides. Vectocell peptides DPV1047 (8a and 12a) and DPV10 (8b and 9b) are able to inhibit the doxorubicin- resistant phenotype of MCF7-Adr cells. However, the compounds 8a and 9b exhibited the greatest cytotoxic activity in the doxorubicin-resistant cell model, although 9b showed a loss of cytotoxic activity in the HCT116 in vitro model (Table 1). The in vitro data therefore suggested that the optimal conjugate for both doxorubicin-sensitive and -resistant models was 8a."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02079	Solid tumor	.	Revealed Based on the Cell Line Data	.	Relative tumor volume	86.20%	%	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The conjugates 8a-c all showed activity; the most active was 8a. Compound 12a showed no activity and confirmed the in vitro data. In a second experiment, conjugates 9c, 9b, and 8a were compared. Compound 9c was completely inactive and 9b was only partially active, which correlated with the reduction of in vitro cytotoxicity of both 9c and 9b compared to 8a observed in the HCT116 model. The in vivo evaluation of the Vectocell-doxorubicin conjugates confirmed that 8a (15 &mu;mol/kg) is the optimal conjugate with a T/C value of 29.5% (Table 1), whereas T/C obtained with the other conjugates ranged from 34.1% (8c) to 86.2% (9c). Moreover, in this experiment, the conjugate 8a (15 &mu;mol/kg) showed better efficacy than doxorubicin (10, 6.5 &mu;mol/kg: doxorubucin's maximal tolerated dose, MTD), with a T/C of 49.6%. It should be noted that it is possible to administer 8a at twice the MTD of doxorubicin (10), demonstrating that 8a is less toxic and more active than 10. For this reason 8a was therefore selected for further preclinical evaluation in both doxorubicin-sensitive and -resistant models."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02080	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	Not detected	.	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02080	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	108 &mu;M	&mu;M	.	.	.	.	Breast cancer	MCF-7/6 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02080	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	500 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7/ADR cell	.	.	Three injections per week for 3 weeks	.	.	"These experiments showed that it is possible to overcome the doxorubicin-resistant phenotype by conjugation of doxorubicin to Vectocell peptides. Vectocell peptides DPV1047 (8a and 12a) and DPV10 (8b and 9b) are able to inhibit the doxorubicin- resistant phenotype of MCF7-Adr cells. However, the compounds 8a and 9b exhibited the greatest cytotoxic activity in the doxorubicin-resistant cell model, although 9b showed a loss of cytotoxic activity in the HCT116 in vitro model (Table 1). The in vitro data therefore suggested that the optimal conjugate for both doxorubicin-sensitive and -resistant models was 8a."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02080	Solid tumor	.	Revealed Based on the Cell Line Data	.	Relative tumor volume	79.70%	%	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The conjugates 8a-c all showed activity; the most active was 8a. Compound 12a showed no activity and confirmed the in vitro data. In a second experiment, conjugates 9c, 9b, and 8a were compared. Compound 9c was completely inactive and 9b was only partially active, which correlated with the reduction of in vitro cytotoxicity of both 9c and 9b compared to 8a observed in the HCT116 model. The in vivo evaluation of the Vectocell-doxorubicin conjugates confirmed that 8a (15 &mu;mol/kg) is the optimal conjugate with a T/C value of 29.5% (Table 1), whereas T/C obtained with the other conjugates ranged from 34.1% (8c) to 86.2% (9c). Moreover, in this experiment, the conjugate 8a (15 &mu;mol/kg) showed better efficacy than doxorubicin (10, 6.5 &mu;mol/kg: doxorubucin's maximal tolerated dose, MTD), with a T/C of 49.6%. It should be noted that it is possible to administer 8a at twice the MTD of doxorubicin (10), demonstrating that 8a is less toxic and more active than 10. For this reason 8a was therefore selected for further preclinical evaluation in both doxorubicin-sensitive and -resistant models."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02081	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	200 &mu;M	&mu;M	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02081	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	114 &mu;M	&mu;M	.	.	.	.	Breast cancer	MCF-7/6 cell	.	.	Three injections per week for 3 weeks	.	.	"The Vectocell peptides alone showed no cytotoxic activity (data not shown). The Vectocell-doxorubicin conjugates 8a-c showed no loss of cytotoxicity compared to free doxorubicin. Compounds 9b and 9c showed a loss of activity in the HCT116 model but not in the MCF-7/6 cell model, compared to free doxorubicin (10). In contrast, the compounds 12a and 12b showed a significant loss of cytotoxicity in both tumor cell lines (loss of 1-2 logs in IC50). The in vitro data, therefore, suggest that the ester (8a-c) and thioether (9b and 9c) bonds are optimal for Vectocell-doxorubicin conjugate activity and that conjugation to the 3 position via an amide bond (12a and 12b) partially inactivates doxorubicin."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02081	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	625 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7/ADR cell	.	.	Three injections per week for 3 weeks	.	.	"These experiments showed that it is possible to overcome the doxorubicin-resistant phenotype by conjugation of doxorubicin to Vectocell peptides. Vectocell peptides DPV1047 (8a and 12a) and DPV10 (8b and 9b) are able to inhibit the doxorubicin- resistant phenotype of MCF7-Adr cells. However, the compounds 8a and 9b exhibited the greatest cytotoxic activity in the doxorubicin-resistant cell model, although 9b showed a loss of cytotoxic activity in the HCT116 in vitro model (Table 1). The in vitro data therefore suggested that the optimal conjugate for both doxorubicin-sensitive and -resistant models was 8a."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00569	PDC_02081	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	Not detected	.	.	.	.	.	Colon carcinoma	HCT 116 cell	.	.	Three injections per week for 3 weeks	.	.	"The conjugates 8a-c all showed activity; the most active was 8a. Compound 12a showed no activity and confirmed the in vitro data. In a second experiment, conjugates 9c, 9b, and 8a were compared. Compound 9c was completely inactive and 9b was only partially active, which correlated with the reduction of in vitro cytotoxicity of both 9c and 9b compared to 8a observed in the HCT116 model. The in vivo evaluation of the Vectocell-doxorubicin conjugates confirmed that 8a (15 &mu;mol/kg) is the optimal conjugate with a T/C value of 29.5% (Table 1), whereas T/C obtained with the other conjugates ranged from 34.1% (8c) to 86.2% (9c). Moreover, in this experiment, the conjugate 8a (15 &mu;mol/kg) showed better efficacy than doxorubicin (10, 6.5 &mu;mol/kg: doxorubucin's maximal tolerated dose, MTD), with a T/C of 49.6%. It should be noted that it is possible to administer 8a at twice the MTD of doxorubicin (10), demonstrating that 8a is less toxic and more active than 10. For this reason 8a was therefore selected for further preclinical evaluation in both doxorubicin-sensitive and -resistant models."	"The conjugation of Vectocell peptides to cytotoxic molecules can modify the in vivo distribution of the therapeutic molecules, improving pharmacokinetic properties and/or reducing systemic toxicity by driving tissue and intracellular delivery.2,5 In addition, conjugation of Vectocell peptides to small molecules/drugs may also provide a means of inhibiting the extracellular export of the therapeutic agents by proteins involved in multidrug resistance (MDR). Multidrug resistance can seriously limit cancer chemotherapy treatment, for example, through the overexpression of membrane transporters that mediate unidirectional energy-dependent drug efflux, thus reducing intracellular drug levels. These membrane transporters are normally expressed in high levels within cells involved in detoxification, such as the liver, kidney, and colon. Tumors arising from these cells are often resistant to chemotherapy treatment from their onset, while other tumors can acquire resistance through the induction of MDR transport proteins during treatment. Many inhibitors of MDR transporters have been identified. However, these inhibitors also interfere with the clearance of the cytotoxic drug, resulting in elevated plasma concentrations of the cytotoxic agent and associated toxicity. An alternative approach is to circumvent rather than to directly inhibit MDR mechanisms, by developing anticancer therapies that are not substrates for extracellular export. Doxorubicin, an anthracycline antibiotic, remains among the most widely used cytotoxic agents for the treatment of a broad spectrum of cancers, including breast, stomach, non-Hodgkin's lymphoma, and bladder cancer. As with many cytotoxic drugs, doxorubicin has severe short- and long-term side effects, in this case mostly associated with bone marrow and myocardial cell toxicity. Cardiotoxicity limits the cumulative dosage of doxorubicin to 500-600 mg/m<sup>2</sup>, which may be a dose at which tumor is still responding to treatment but for which no further doxorubicin treatment can be given. Another drawback of doxorubicin is the emergence of drug resistance that results in the reduction of the intracellular concentration of doxorubicin. The present study aimed to generate novel peptidic-doxorubicin conjugates by use of three Vectocell peptides that differ in terms of their charge, size, and intracellular delivery characteristics and to assess their ability to enhance the therapeutic potential of doxorubicin and to prevent the appearance of MDR. Different conjugation sites and linkers of different stabilities were used to generate Vectocell-doxorubicin conjugates in order to evaluate their effect on efficacy. Chemical routes were developed to allow the conjugation of doxorubicin to Vectocell peptides through ester, thioether, and amide chemical linkers. The ester and thioether involved carbon 14 of doxorubicin, and the amide carbon 3. In vitro and in vivo characterization has defined the optimal conjugate-linker combination that significantly increases efficacy above unconjugated doxorubicin in both doxorubicin-sensitive and -resistant models. The data presented therefore provide in vivo proof of concept for the use of Vectocell peptides to improve the therapeutic index of doxorubicin, and potentially many other cytotoxic or small molecule anticancer drugs."
REF00568	PDC_02082	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	100.00%	%	.	.	.	.	Askin tumor 	SK-N-MC cell	.	.	48 h	1 &mu;M	XTT assay	"[C15]-NPY, [C15]-NPY-Dauno-MBS, and [C15]-NPY-Doxo-MBS showed no or only marginal effects. In contrast, [C15]-NPY-Dauno-HYD was as effective as free daunorubicin with respect to cytotoxicity, and the compounds were able to reduce cell growth by 66.9 &plusmn; 2.5% and 68.6 &plusmn; 0.4%, respectively."	"In this study, we investigate the usefulness of peptides as carriers for which the receptors are overexpressed on tumor cells. Covalent linking of the drug to the peptide could be used for chemotherapy and would lead to selective addressing of the tumor cells. As a model peptide, we used neuropeptide Y (NPY) because its receptors are produced in a number of neuroblastoma and the thereof derived cell lines. NPY is a 36-amino acid peptide of the pancreatic polypeptide family. It is expressed in the peripheral and central nervous systems and is one of the most abundant neuropeptides in the brain. Five distinct NPY receptors have been cloned, which have been named Y1, Y2, Y4, Y5, and y6 receptor subtypes. Upon binding to the G-protein coupled receptors, the ligand-receptor complex is internalized, which provides a convenient way to enter the cell by receptor-mediated endocytosis. Because structure-activity relationships (SARs) of NPY are well-known, position 15 of NPY was used for attaching maleimide anthracycline derivatives which would presumably not lead to a significant loss of binding activity for the Y1 receptor. Because the NPY-receptor complex is internalized and undergoes a pH shift from 7.4 to approximately 5.0 during endosomal trafficking, two different anthracycline derivatives that differ in the acid sensitivity of the bond between the drug and the spacer were selected (see Figure 1). Doxo-MBS and Dauno-MBS are characterized by a stable amide bond at the 3-amino position of the anthracycline; Dauno-HYD is a daunorubicin derivative incorporating an acid-sensitive hydrazone linker at the 13-keto position. The maleimide moiety was introduced into daunorubicin and doxorubicin in order to selectively label the sulfhydryl group of [C15]-NPY."
REF00568	PDC_02082	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	100.00%	%	.	.	.	.	Askin tumor 	SK-N-MC cell	.	.	36 h	1 &mu;M with BIBP 3226 (100 &mu;M)	.	"Pretreatment with 100 &mu;M of the Y1 receptor antagonist BIBP 322629,30 antagonized the cytotoxicity of [C15]-NPY-Dauno-HYD (cell viability remained at 89.1 &plusmn; 4.6%), but not that of daunorubicin. To investigate the minimal required concentration of the administered conjugates, dilutions were made and tested on SK-N-MC cells; the cytotoxic effects of [C15]-NPY-Dauno-HYD and daunorubicin were visible starting at 1 &mu;M concentrations."	"In this study, we investigate the usefulness of peptides as carriers for which the receptors are overexpressed on tumor cells. Covalent linking of the drug to the peptide could be used for chemotherapy and would lead to selective addressing of the tumor cells. As a model peptide, we used neuropeptide Y (NPY) because its receptors are produced in a number of neuroblastoma and the thereof derived cell lines. NPY is a 36-amino acid peptide of the pancreatic polypeptide family. It is expressed in the peripheral and central nervous systems and is one of the most abundant neuropeptides in the brain. Five distinct NPY receptors have been cloned, which have been named Y1, Y2, Y4, Y5, and y6 receptor subtypes. Upon binding to the G-protein coupled receptors, the ligand-receptor complex is internalized, which provides a convenient way to enter the cell by receptor-mediated endocytosis. Because structure-activity relationships (SARs) of NPY are well-known, position 15 of NPY was used for attaching maleimide anthracycline derivatives which would presumably not lead to a significant loss of binding activity for the Y1 receptor. Because the NPY-receptor complex is internalized and undergoes a pH shift from 7.4 to approximately 5.0 during endosomal trafficking, two different anthracycline derivatives that differ in the acid sensitivity of the bond between the drug and the spacer were selected (see Figure 1). Doxo-MBS and Dauno-MBS are characterized by a stable amide bond at the 3-amino position of the anthracycline; Dauno-HYD is a daunorubicin derivative incorporating an acid-sensitive hydrazone linker at the 13-keto position. The maleimide moiety was introduced into daunorubicin and doxorubicin in order to selectively label the sulfhydryl group of [C15]-NPY."
REF00568	PDC_02083	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	35.00%	%	.	.	.	.	Askin tumor 	SK-N-MC cell	.	.	48 h	1 &mu;M	XTT assay	"[C15]-NPY, [C15]-NPY-Dauno-MBS, and [C15]-NPY-Doxo-MBS showed no or only marginal effects. In contrast, [C15]-NPY-Dauno-HYD was as effective as free daunorubicin with respect to cytotoxicity, and the compounds were able to reduce cell growth by 66.9 &plusmn; 2.5% and 68.6 &plusmn; 0.4%, respectively."	"In this study, we investigate the usefulness of peptides as carriers for which the receptors are overexpressed on tumor cells. Covalent linking of the drug to the peptide could be used for chemotherapy and would lead to selective addressing of the tumor cells. As a model peptide, we used neuropeptide Y (NPY) because its receptors are produced in a number of neuroblastoma and the thereof derived cell lines. NPY is a 36-amino acid peptide of the pancreatic polypeptide family. It is expressed in the peripheral and central nervous systems and is one of the most abundant neuropeptides in the brain. Five distinct NPY receptors have been cloned, which have been named Y1, Y2, Y4, Y5, and y6 receptor subtypes. Upon binding to the G-protein coupled receptors, the ligand-receptor complex is internalized, which provides a convenient way to enter the cell by receptor-mediated endocytosis. Because structure-activity relationships (SARs) of NPY are well-known, position 15 of NPY was used for attaching maleimide anthracycline derivatives which would presumably not lead to a significant loss of binding activity for the Y1 receptor. Because the NPY-receptor complex is internalized and undergoes a pH shift from 7.4 to approximately 5.0 during endosomal trafficking, two different anthracycline derivatives that differ in the acid sensitivity of the bond between the drug and the spacer were selected (see Figure 1). Doxo-MBS and Dauno-MBS are characterized by a stable amide bond at the 3-amino position of the anthracycline; Dauno-HYD is a daunorubicin derivative incorporating an acid-sensitive hydrazone linker at the 13-keto position. The maleimide moiety was introduced into daunorubicin and doxorubicin in order to selectively label the sulfhydryl group of [C15]-NPY."
REF00568	PDC_02083	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	100.00%	%	.	.	.	.	Glioblastoma	XF 498 cell	.	.	48 h	1 &mu;M	.	"The same compounds were tested on glioblastoma XF-498L cells that do not express NPY receptors.31 Daunorubicin was able to reduce cell growth by 47.3 &plusmn; 5%, whereas [C15]-NPY-Dauno-HYD showed no cytotoxicity (Figure 3C)."	"In this study, we investigate the usefulness of peptides as carriers for which the receptors are overexpressed on tumor cells. Covalent linking of the drug to the peptide could be used for chemotherapy and would lead to selective addressing of the tumor cells. As a model peptide, we used neuropeptide Y (NPY) because its receptors are produced in a number of neuroblastoma and the thereof derived cell lines. NPY is a 36-amino acid peptide of the pancreatic polypeptide family. It is expressed in the peripheral and central nervous systems and is one of the most abundant neuropeptides in the brain. Five distinct NPY receptors have been cloned, which have been named Y1, Y2, Y4, Y5, and y6 receptor subtypes. Upon binding to the G-protein coupled receptors, the ligand-receptor complex is internalized, which provides a convenient way to enter the cell by receptor-mediated endocytosis. Because structure-activity relationships (SARs) of NPY are well-known, position 15 of NPY was used for attaching maleimide anthracycline derivatives which would presumably not lead to a significant loss of binding activity for the Y1 receptor. Because the NPY-receptor complex is internalized and undergoes a pH shift from 7.4 to approximately 5.0 during endosomal trafficking, two different anthracycline derivatives that differ in the acid sensitivity of the bond between the drug and the spacer were selected (see Figure 1). Doxo-MBS and Dauno-MBS are characterized by a stable amide bond at the 3-amino position of the anthracycline; Dauno-HYD is a daunorubicin derivative incorporating an acid-sensitive hydrazone linker at the 13-keto position. The maleimide moiety was introduced into daunorubicin and doxorubicin in order to selectively label the sulfhydryl group of [C15]-NPY."
REF00568	PDC_02083	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	60.00%	%	.	.	.	.	Askin tumor 	SK-N-MC cell	.	.	36 h	1 &mu;M with BIBP 3226 (100 &mu;M)	.	"Pretreatment with 100 &mu;M of the Y1 receptor antagonist BIBP 322629,30 antagonized the cytotoxicity of [C15]-NPY-Dauno-HYD (cell viability remained at 89.1 &plusmn; 4.6%), but not that of daunorubicin. To investigate the minimal required concentration of the administered conjugates, dilutions were made and tested on SK-N-MC cells; the cytotoxic effects of [C15]-NPY-Dauno-HYD and daunorubicin were visible starting at 1 &mu;M concentrations."	"In this study, we investigate the usefulness of peptides as carriers for which the receptors are overexpressed on tumor cells. Covalent linking of the drug to the peptide could be used for chemotherapy and would lead to selective addressing of the tumor cells. As a model peptide, we used neuropeptide Y (NPY) because its receptors are produced in a number of neuroblastoma and the thereof derived cell lines. NPY is a 36-amino acid peptide of the pancreatic polypeptide family. It is expressed in the peripheral and central nervous systems and is one of the most abundant neuropeptides in the brain. Five distinct NPY receptors have been cloned, which have been named Y1, Y2, Y4, Y5, and y6 receptor subtypes. Upon binding to the G-protein coupled receptors, the ligand-receptor complex is internalized, which provides a convenient way to enter the cell by receptor-mediated endocytosis. Because structure-activity relationships (SARs) of NPY are well-known, position 15 of NPY was used for attaching maleimide anthracycline derivatives which would presumably not lead to a significant loss of binding activity for the Y1 receptor. Because the NPY-receptor complex is internalized and undergoes a pH shift from 7.4 to approximately 5.0 during endosomal trafficking, two different anthracycline derivatives that differ in the acid sensitivity of the bond between the drug and the spacer were selected (see Figure 1). Doxo-MBS and Dauno-MBS are characterized by a stable amide bond at the 3-amino position of the anthracycline; Dauno-HYD is a daunorubicin derivative incorporating an acid-sensitive hydrazone linker at the 13-keto position. The maleimide moiety was introduced into daunorubicin and doxorubicin in order to selectively label the sulfhydryl group of [C15]-NPY."
REF00568	PDC_02084	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	90.00%	%	.	.	.	.	Askin tumor 	SK-N-MC cell	.	.	48 h	1 &mu;M	XTT assay	"[C15]-NPY, [C15]-NPY-Dauno-MBS, and [C15]-NPY-Doxo-MBS showed no or only marginal effects. In contrast, [C15]-NPY-Dauno-HYD was as effective as free daunorubicin with respect to cytotoxicity, and the compounds were able to reduce cell growth by 66.9 &plusmn; 2.5% and 68.6 &plusmn; 0.4%, respectively."	"In this study, we investigate the usefulness of peptides as carriers for which the receptors are overexpressed on tumor cells. Covalent linking of the drug to the peptide could be used for chemotherapy and would lead to selective addressing of the tumor cells. As a model peptide, we used neuropeptide Y (NPY) because its receptors are produced in a number of neuroblastoma and the thereof derived cell lines. NPY is a 36-amino acid peptide of the pancreatic polypeptide family. It is expressed in the peripheral and central nervous systems and is one of the most abundant neuropeptides in the brain. Five distinct NPY receptors have been cloned, which have been named Y1, Y2, Y4, Y5, and y6 receptor subtypes. Upon binding to the G-protein coupled receptors, the ligand-receptor complex is internalized, which provides a convenient way to enter the cell by receptor-mediated endocytosis. Because structure-activity relationships (SARs) of NPY are well-known, position 15 of NPY was used for attaching maleimide anthracycline derivatives which would presumably not lead to a significant loss of binding activity for the Y1 receptor. Because the NPY-receptor complex is internalized and undergoes a pH shift from 7.4 to approximately 5.0 during endosomal trafficking, two different anthracycline derivatives that differ in the acid sensitivity of the bond between the drug and the spacer were selected (see Figure 1). Doxo-MBS and Dauno-MBS are characterized by a stable amide bond at the 3-amino position of the anthracycline; Dauno-HYD is a daunorubicin derivative incorporating an acid-sensitive hydrazone linker at the 13-keto position. The maleimide moiety was introduced into daunorubicin and doxorubicin in order to selectively label the sulfhydryl group of [C15]-NPY."
REF00568	PDC_02084	Solid tumor	.	Revealed Based on the Cell Line Data	High Expreesion	Cell viability	98.00%	%	.	.	.	.	Askin tumor 	SK-N-MC cell	.	.	36 h	1 &mu;M with BIBP 3226 (100 &mu;M)	.	"Pretreatment with 100 &mu;M of the Y1 receptor antagonist BIBP 322629,30 antagonized the cytotoxicity of [C15]-NPY-Dauno-HYD (cell viability remained at 89.1 &plusmn; 4.6%), but not that of daunorubicin. To investigate the minimal required concentration of the administered conjugates, dilutions were made and tested on SK-N-MC cells; the cytotoxic effects of [C15]-NPY-Dauno-HYD and daunorubicin were visible starting at 1 &mu;M concentrations."	"In this study, we investigate the usefulness of peptides as carriers for which the receptors are overexpressed on tumor cells. Covalent linking of the drug to the peptide could be used for chemotherapy and would lead to selective addressing of the tumor cells. As a model peptide, we used neuropeptide Y (NPY) because its receptors are produced in a number of neuroblastoma and the thereof derived cell lines. NPY is a 36-amino acid peptide of the pancreatic polypeptide family. It is expressed in the peripheral and central nervous systems and is one of the most abundant neuropeptides in the brain. Five distinct NPY receptors have been cloned, which have been named Y1, Y2, Y4, Y5, and y6 receptor subtypes. Upon binding to the G-protein coupled receptors, the ligand-receptor complex is internalized, which provides a convenient way to enter the cell by receptor-mediated endocytosis. Because structure-activity relationships (SARs) of NPY are well-known, position 15 of NPY was used for attaching maleimide anthracycline derivatives which would presumably not lead to a significant loss of binding activity for the Y1 receptor. Because the NPY-receptor complex is internalized and undergoes a pH shift from 7.4 to approximately 5.0 during endosomal trafficking, two different anthracycline derivatives that differ in the acid sensitivity of the bond between the drug and the spacer were selected (see Figure 1). Doxo-MBS and Dauno-MBS are characterized by a stable amide bond at the 3-amino position of the anthracycline; Dauno-HYD is a daunorubicin derivative incorporating an acid-sensitive hydrazone linker at the 13-keto position. The maleimide moiety was introduced into daunorubicin and doxorubicin in order to selectively label the sulfhydryl group of [C15]-NPY."
REF00619	PDC_02088	Pancreatic carcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	31.50 &plusmn; 1.74 &mu;M	&mu;M	.	.	.	.	Pancreatic ductal adenocarcinoma	MIA PaCa-2 cell	.	.	72 h	.	CellTiter-Glo cell proliferation assay	"We selected cells, where doxorubicin is typically applied and which overexpress somatostatin receptors, like the human pancreatic carcinoma cell line MIA PaCa-2 or MCF-7. Doxorubicins antiproliferative action on MIA PaCa-2 after 72 h incubation with the drug was as expected very strong (IC50 = 0.80 &plusmn; 0.13 &mu;M), whereas octreotide was not able to inhibit cell growth by 50% up to a concentration of 150 &mu;M. The cytotoxic effects of the conjugate expressed, as half maximal inhibitory concentration was much stronger compared to the precursor peptide, but, nevertheless, lower than that of doxorubicin (IC50 = 31.50 &plusmn; 1.74 &mu;M). This characteristic feature of 12 is attributed to the different cellular uptake mechanisms of the substances. Doxorubicin is taken up quickly by passive diffusion, while octreotide enters cells by receptor-mediated endocytosis. Furthermore, it needs to be considered that the conjugate releases after cleavage by glutathione a doxorubicin derivative, which is still carrying a small cross-linker residue. Previous studies have shown that these types of molecules are, nevertheless, capable of successfully interacting with DNA, to mediate their cytotoxic properties, but to a lesser extent."	"In the present work, we introduce a new approach to overcome all the aforementioned limitations. The cytotoxic drug doxorubicin is coupled to the tumor-targeting vector octreotide via a disulfide-intercalating cross-linking reagent. On the one hand, this reagent creates an oxime bond with the drug, and on the other hand, two disulfides with octreotide to keep the cyclic structure of the peptide. The combination of a hydrolytically stable oxime bond and disulfides leads to the formation of a novel bioconjugate superior to any previous anticancer drug-somatostatin analog hybrid as it allows the efficient release of the toxic cargo within the reducing environment of cancer cells. The versatility of the linker molecule described here will enable its future application not only in targeted drug delivery, but also in the chemical modification of therapeutic proteins."
REF00619	PDC_02088	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	27.14 &plusmn; 2.47 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	72 h	.	CellTiter-Glo cell proliferation assay	"We selected cells, where doxorubicin is typically applied and which overexpress somatostatin receptors, like the human pancreatic carcinoma cell line MIA PaCa-2 or MCF-7. Doxorubicins antiproliferative action on MIA PaCa-2 after 72 h incubation with the drug was as expected very strong (IC50 = 0.80 &plusmn; 0.13 &mu;M), whereas octreotide was not able to inhibit cell growth by 50% up to a concentration of 150 &mu;M. The cytotoxic effects of the conjugate expressed, as half maximal inhibitory concentration was much stronger compared to the precursor peptide, but, nevertheless, lower than that of doxorubicin (IC50 = 31.50 &plusmn; 1.74 &mu;M). This characteristic feature of 12 is attributed to the different cellular uptake mechanisms of the substances. Doxorubicin is taken up quickly by passive diffusion, while octreotide enters cells by receptor-mediated endocytosis. Furthermore, it needs to be considered that the conjugate releases after cleavage by glutathione a doxorubicin derivative, which is still carrying a small cross-linker residue. Previous studies have shown that these types of molecules are, nevertheless, capable of successfully interacting with DNA, to mediate their cytotoxic properties, but to a lesser extent."	"In the present work, we introduce a new approach to overcome all the aforementioned limitations. The cytotoxic drug doxorubicin is coupled to the tumor-targeting vector octreotide via a disulfide-intercalating cross-linking reagent. On the one hand, this reagent creates an oxime bond with the drug, and on the other hand, two disulfides with octreotide to keep the cyclic structure of the peptide. The combination of a hydrolytically stable oxime bond and disulfides leads to the formation of a novel bioconjugate superior to any previous anticancer drug-somatostatin analog hybrid as it allows the efficient release of the toxic cargo within the reducing environment of cancer cells. The versatility of the linker molecule described here will enable its future application not only in targeted drug delivery, but also in the chemical modification of therapeutic proteins."
REF00619	PDC_02088	Pancreatic adenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	48.90 &plusmn; 5.40 &mu;M	&mu;M	.	.	.	.	Pancreatic ductal adenocarcinoma	Capan-1 cell	.	.	72 h	.	CellTiter-Glo cell proliferation assay	"We selected cells, where doxorubicin is typically applied and which overexpress somatostatin receptors, like the human pancreatic carcinoma cell line MIA PaCa-2 or MCF-7. Doxorubicins antiproliferative action on MIA PaCa-2 after 72 h incubation with the drug was as expected very strong (IC50 = 0.80 &plusmn; 0.13 &mu;M), whereas octreotide was not able to inhibit cell growth by 50% up to a concentration of 150 &mu;M. The cytotoxic effects of the conjugate expressed, as half maximal inhibitory concentration was much stronger compared to the precursor peptide, but, nevertheless, lower than that of doxorubicin (IC50 = 31.50 &plusmn; 1.74 &mu;M). This characteristic feature of 12 is attributed to the different cellular uptake mechanisms of the substances. Doxorubicin is taken up quickly by passive diffusion, while octreotide enters cells by receptor-mediated endocytosis. Furthermore, it needs to be considered that the conjugate releases after cleavage by glutathione a doxorubicin derivative, which is still carrying a small cross-linker residue. Previous studies have shown that these types of molecules are, nevertheless, capable of successfully interacting with DNA, to mediate their cytotoxic properties, but to a lesser extent."	"In the present work, we introduce a new approach to overcome all the aforementioned limitations. The cytotoxic drug doxorubicin is coupled to the tumor-targeting vector octreotide via a disulfide-intercalating cross-linking reagent. On the one hand, this reagent creates an oxime bond with the drug, and on the other hand, two disulfides with octreotide to keep the cyclic structure of the peptide. The combination of a hydrolytically stable oxime bond and disulfides leads to the formation of a novel bioconjugate superior to any previous anticancer drug-somatostatin analog hybrid as it allows the efficient release of the toxic cargo within the reducing environment of cancer cells. The versatility of the linker molecule described here will enable its future application not only in targeted drug delivery, but also in the chemical modification of therapeutic proteins."
REF00621	PDC_02117	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	.	Tumor Growth Inhibition value (TGI)	75%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	30 days	2.5 mg DOX equivalent/kg	.	"After the tumor xenografts reached a volume of around 100150 mm<sup>3</sup>, mice were randomized into three groups (n = 7), namely, saline (negative control), free doxorubicin (positive control), and hydrazone PDC. A low dose of 2.5 mg/kg Dox or 2.5 mg/kg Dox equivalent for PDC was chosen to study the antitumor efficacy in vivo. Mice were intravenously administered treatment by tail vein every seventh day for six doses. Compared to the saline group, the PDC reduced tumor growth significantly (3.8 times) on day 35 after treatment, whereas the reduction of tumor growth after free Dox treatment was 2.5 times, suggesting the PDC, at the same equivalent dose, was more potent than the free Dox. In addition, the mice treated with PDC remained in overall good health condition, as evidenced by the general appearance, behavior, diet consumption, and body weight. On day 32 during the treatment period, there were no significant differences observed between the PDC and saline groups in the average body weight (p > 0.05). However, the mice treated with Dox showed significant body weight loss (reduced by 11.2%) compared to the PDC group. Twenty-four hours after the last treatment with PDC or free Dox, mice were euthanized. Mice treated with saline were euthanized on day 32 because of the tumor size per IACUC policy and the conditions for euthanasia. Tumor and other major tissues were collected and weighted for further analysis. The mice with PDC treatment exhibited a greater reduction (three times reduction compared to saline) of tumor weight compared to that of free Dox treated (two times reduction compared to saline)."	"Keratin 1 (K1) is a novel receptor, present on the surface of cancer cells (breast and neuroblastoma) and cells that have undergone oxidative stress, that is being used for targeted drug delivery. We showed that K1 is present on the surface of MCF-7 breast cancer cells, and a comparison of the total K1 levels in cell lysates using Western blot showed that cancer cells (MCF-7 and MDA-MB-435) have a much higher expression of K1 compared to non-cancerous breast tissue derived epithelial (MCF-10A) cells. We engineered peptides, such as linear 18-4 and cyclic analogues, for specific uptake by breast cancer cells (MCF-7 and MDA-MB-231) via cell surface K1 mediated endocytosis. Further, K1 targeting linear peptide 18-4 was used to synthesize four peptide-doxorubicin conjugates with different linker chemistries, such as ester, amide, succinimidyl thioether, and hydrazone. We showed specific uptake of the targeted PDCs via receptor mediated endocytosis in MCF-7 and MDA-MB-435-MDR cancer cells. The PDCs with K1 targeting peptide 18-4 were more cytotoxic to TNBC cells (IC50 1.2-4.7 &mu;M) compared to non-cancerous human mammary epithelial MCF-10A cells (IC50 15.1-38.6 &mu;M), while free drug (doxorubicin) was equally cytotoxic to both cancer and non-cancerous cells (IC50 0.24-1.5 &mu;M). To explore the in vivo efficacy and evaluate the potential of K1 targeting PDC for TNBC treatment, we report here the antitumor activity of one of these peptide-doxorubicin conjugates, where the peptide (18-4) is conjugated to Dox via an acid-sensitive N-acyl hydrazone linker in a mouse model for TNBC. TNBC MDA-MB-231 cells were subcutaneously injected into female NOD/SCID mice to generate TNBC cell-derived xenograft models. Mice treated with the conjugate showed better efficacy, pharmacokinetics, and safety profile compared to the Dox treated mice, supporting the future clinical development of K1 targeted PDCs for treatment of TNBC."
REF00623	PDC_02118	Ovarian serous cystadenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	5.45 &plusmn; 0.41 &mu;M	&mu;M	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	72 h	.	CCK8 assay	"Cell Counting Kit-8 (CCK8) was used to evaluate the in vitro anti-tumor activity and selectivity of Sal-A6 cell viability inhibitory effect of Sal, A6, compound E, and Sal-A6 was assessed in both CD44+ SKOV3 and CD44? A2780 cells. The results showed that peptide A6 exhibited no significant inhibitory effect on any tumor cells, in line with literature reports. Conversely, Sal and compound E significantly inhibited tumor cells proliferation while Sal-A6 conjugate exhibited the ability to suppress the cell viability of CD44+ SKOV3, demonstrating superior activity compared to Sal. However, it showed no significant inhibitory effect on CD44? A2780 cells, exerting only a moderate effect under high concentration conditions, possibly due to the target-mediated cellular entry of Sal-A6. To further validate whether the cytotoxicity of Sal-A6 is related to targeting via CD44, CD44+ SKOV3 cells co-incubated with A6 peptide and Sal-A6 at concentrations of 100 &mu;M and 10 &mu;M, respectively. Peptide A6 partially alleviated the cytotoxicity of Sal-A6, especially at saturated concentration (100 &mu;M), leading to a significant reduction in the in vitro activity of Sal-A6 at both low (10 &mu;M) and high (100 &mu;M) concentrations. These results suggest that cells with low CD44 expression or treated with peptide A6 can mitigate the cellular inhibitory effects of Sal-A6. The onset of action of Sal-A6 was slower than that of Sal, which may be due to the fact that Sal-A6 exerts its efficacy through receptor-mediated entry into the cell and has a slower onset of action than the highly fat-soluble Sal. Overall, the competitive binding of cells with low CD44 expression and peptide A6 confirms that the in vitro activity of Sal-A6 is related to CD44 expression."	"In this study, a disulfide bond was employed as a linker to couple peptide A6 with Sal, yielding the novel conjugate Sal-A6. Compared to Sal, Sal-A6 not only displayed increased activity and solubility but also demonstrated a notable improvement in targeting specificity. Additionally, Sal-A6 can overcome drug-resistance in cells, leading to a sensitization effect. Surprisingly, Sal-A6 also exhibited a bystander killing effect, capable of eliminating tumor cells with low CD44 expression. Furthermore, at lower doses, it exerts antitumor effects in vivo. The glutathione (GSH) content in tumor cells resistant to cisplatin (CDDP) is significantly higher than that in non-resistant tumor cells. GSH possesses a strong binding affinity with CDDP, resulting in the inactivation of CDDP. Nevertheless, Sal can effectively decrease the intracellular GSH content in tumor cells and elevate the level of intracellular reactive oxygen species (ROS). Moreover, the disulfide bond utilized in Sal-A6 can efficiently diminish the intra-cellular GSH content, thereby overcoming cellular resistance to CDDP and improving drug sensitivity."
REF00623	PDC_02118	Ovarian endometrioid adenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	47.09 &plusmn; 2.69 &mu;M	&mu;M	.	.	.	.	Ovarian endometrioid adenocarcinoma	A2780 cell	.	.	72 h	.	CCK8 assay	"Cell Counting Kit-8 (CCK8) was used to evaluate the in vitro anti-tumor activity and selectivity of Sal-A6 cell viability inhibitory effect of Sal, A6, compound E, and Sal-A6 was assessed in both CD44+ SKOV3 and CD44? A2780 cells. The results showed that peptide A6 exhibited no significant inhibitory effect on any tumor cells, in line with literature reports. Conversely, Sal and compound E significantly inhibited tumor cells proliferation while Sal-A6 conjugate exhibited the ability to suppress the cell viability of CD44+ SKOV3, demonstrating superior activity compared to Sal. However, it showed no significant inhibitory effect on CD44? A2780 cells, exerting only a moderate effect under high concentration conditions, possibly due to the target-mediated cellular entry of Sal-A6. To further validate whether the cytotoxicity of Sal-A6 is related to targeting via CD44, CD44+ SKOV3 cells co-incubated with A6 peptide and Sal-A6 at concentrations of 100 &mu;M and 10 &mu;M, respectively. Peptide A6 partially alleviated the cytotoxicity of Sal-A6, especially at saturated concentration (100 &mu;M), leading to a significant reduction in the in vitro activity of Sal-A6 at both low (10 &mu;M) and high (100 &mu;M) concentrations. These results suggest that cells with low CD44 expression or treated with peptide A6 can mitigate the cellular inhibitory effects of Sal-A6. The onset of action of Sal-A6 was slower than that of Sal, which may be due to the fact that Sal-A6 exerts its efficacy through receptor-mediated entry into the cell and has a slower onset of action than the highly fat-soluble Sal. Overall, the competitive binding of cells with low CD44 expression and peptide A6 confirms that the in vitro activity of Sal-A6 is related to CD44 expression."	"In this study, a disulfide bond was employed as a linker to couple peptide A6 with Sal, yielding the novel conjugate Sal-A6. Compared to Sal, Sal-A6 not only displayed increased activity and solubility but also demonstrated a notable improvement in targeting specificity. Additionally, Sal-A6 can overcome drug-resistance in cells, leading to a sensitization effect. Surprisingly, Sal-A6 also exhibited a bystander killing effect, capable of eliminating tumor cells with low CD44 expression. Furthermore, at lower doses, it exerts antitumor effects in vivo. The glutathione (GSH) content in tumor cells resistant to cisplatin (CDDP) is significantly higher than that in non-resistant tumor cells. GSH possesses a strong binding affinity with CDDP, resulting in the inactivation of CDDP. Nevertheless, Sal can effectively decrease the intracellular GSH content in tumor cells and elevate the level of intracellular reactive oxygen species (ROS). Moreover, the disulfide bond utilized in Sal-A6 can efficiently diminish the intra-cellular GSH content, thereby overcoming cellular resistance to CDDP and improving drug sensitivity."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	3.9 nM	nM	.	.	.	.	HIV infection	IIIB HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	4.8 nM	nM	.	.	.	.	HIV infection	SLKA HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	0.9 nM	nM	.	.	.	.	HIV infection	RW/92/016 HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	0.5 nM	nM	.	.	.	.	HIV infection	BR/92/025 HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	4.2 nM	nM	.	.	.	.	HIV infection	JV1083 HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	0.8 nM	nM	.	.	.	.	HIV infection	302056 HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	1.6 nM	nM	.	.	.	.	HIV infection	CMU02 HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	5 nM	nM	.	.	.	.	HIV infection	MDR 769 HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Half Maximal Effect Concentration (EC50)	2.7 nM	nM	.	.	.	.	HIV infection	Avg HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	"6,345"	.	.	.	.	.	HIV infection	IIIB HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	208	.	.	.	.	.	HIV infection	SLKA HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	1149	.	.	.	.	.	HIV infection	RW/92/016 HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	1961	.	.	.	.	.	HIV infection	BR/92/025 HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	240	.	.	.	.	.	HIV infection	JV1083 HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	1235	.	.	.	.	.	HIV infection	302056 HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	621	.	.	.	.	.	HIV infection	CMU02 HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Selectivity index	202	.	.	.	.	.	HIV infection	MDR 769 HIV-1 isolate	.	.	6 days	.	PBMC assay	"After demonstrating the in vivo albumin conjugation of FB006M and its long half-life, we further examined the anti-HIV activity of albumin-FB006M conjugate. We first examined the in vitro anti-HIV activities of FB006 and FB006M-HSA conjugate in a PBMC assay. The assay used subtype B, A, C, G, and EA HIV-1 viruses, utilizing either CXCR4 or CCR5 coreceptor. The activity against HIV-1MDR 769, a clinical isolate resistant to most of the HIV reverse transcriptase and protease inhibitors, also was determined. Both FB006 and FB006M-HSA conjugate exhibited potent activity, with average 50% effective concentrations (EC50s) of 1.4 and 2.7 nM, respectively. Interestingly, the FB006M-HSA conjugate, in which FB006 was linked to albumin at the 13th lysine residue by a linker molecule, showed anti-HIV activities similar to those of free peptide FB006."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00617	PDC_02119	Human immunodeficiency virus infection	.	Revealed Based on the Cell Line Data	.	Control rate	5.5 &plusmn; 4.9%	%	.	.	.	.	HIV infection	NL4-3 HIV isolate	.	.	21 days	10 mg/kg/day	.	"The in vivo efficacy of FB006M was studied in a SCID/hu Thy/Liv mouse model of HIV-1 infection. Homozygous immunodeficient C.B-17-SCID mice were implanted under the left kidney capsule with human fetal thymus and liver tissues from a single donor 20 weeks before inoculation with HIV-1. FB006M was administered by subcutaneous injection at 10 mg/kg per day, beginning 1 day before the direct inoculation of each implant with 1,000 TCID50 of HIV-1NL4-3. FB006 and lamivudine (3TC) were used as controls. The dose selected for the study was based on the observed effective dose of approved AIDS drugs in this model. Because mouse albumin has a half-life of approximately 12 h and the albumin-FB006M conjugate was expected to show a half-life similar to that of albumin, the dosing frequency was set to once daily and once every 2 days. When given by once-daily injection, both FB006 and FB006M showed potent antiviral activity. No p24 antigen was detected in the implants of seven mice treated with 10 mg/kg/day FB006M, and viral RNA was reduced by 3.0 log10 compared to results for untreated mice. When the treatment was once every other day, FB006M reduced p24 by 95% and HIV-1 RNA by 1.5 log10, while FB006 showed no statistically significant activity."	"Based on these considerations, we set out the program with the peptide HIV-1 fusion inhibitor C34, a 34-amino-acid peptide from the C-terminal heptad repeat region of HIV-1 gp41 envelope protein. At its C terminus, C34 shares an identical 24-amino-acid sequence with the N terminus of enfuvirtide. Nevertheless, these two peptides are believed to utilize nonoverlapping molecular targets in the HIV-1 membrane glycoprotein gp41. Assisted by the crystal structure of C34 in complex with HIV-1 gp41 N peptides, three residues of C34 not involved in target binding were replaced by lysine and glutamic acid to improve the solubility and antiviral activity. This peptide, FB006, is to be chemically modified further and conjugated to albumin. Albumins of rodents, rabbits, dogs, monkeys, and humans all possess a conserved cysteine residue (Cys34 in humans) that has the only free thiol group in the protein. To enable binding to this thiol group, FB006 was modified by 3-maleimidopropionic acid (MPA), which allows an irreversible reaction between the maleimide and the free thiol to form a specific 1:1 peptide-albumin conjugate. Guided by the crystal structure of the HIV-1 gp41 ectodomain, we chemically modified FB006 with a single MPA at different residual positions. These peptides were conjugated to human serum albumin (HSA) in vitro and subjected to a human peripheral blood mononuclear cell (PBMC) assay to determine their anti-HIV activities. Based on the results, a lead molecule named FB006M was selected for further studies."
REF00622	PDC_02125	Glioblastoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	7.5 &plusmn; 0.9 nM	nM	.	.	.	.	Glioblastoma	U-87MG cell	.	.	72 h	.	MTT assay	"In a first instance we performed an in vitro antiproliferative assay in which the different cell lines were incubated with different concentrations of the conjugate 2 for 72 h. As reported in Figure 3, 2 showed a potent antitumor activity in a low nanomolar range, from 3.7 to 70.4 nM depending on the cancer cell line, whereas the treatment with the free drug MMAE led to an antitumor activity of 0.03 nM for SK-OV-3 and of 0.23 nM for U87MG, and in very low nanomolar range on SK-MEL-28 cell line. Interestingly, the relative potency (RP) of the conjugate, normalized with respect to MMAE (i.e., the ratio of the IC50 values of 2 vs. MMAE) in U87MG cancer cell line after 72 h was much lower than the one observed with the previously reported cyclo[DKP-isoDGR]-PEG4-VA-PABC-MMAE (33-fold loss of potency vs. 151-fold loss of potency, respectively) bearing the VA linker. This data could suggest a positive effect of the GPLG cleavable linker on the release of the MMAE. Furthermore, a drop of potency between the free drug and the conjugate can be noticed in A549 from the RP value, where the integrin receptor level is significantly lower than in the other cancer cell lines. To better explore the targeting ability of the conjugate 2 towards different level of integrin expression, we decided to further evaluate the antiproliferative activity of the GPLG-conjugate by changing the incubation time."	"Here, we show that the replacement of the Val-Ala-p-aminobenzyloxycarbamate linker with the Gly-Pro-Leu-Gly-p-aminobenzyloxycarbamate (GPLG-PABC) sequence as enzymatically cleavable linker in the SMDC bearing the cyclo[DKP-isoDGR] &alpha;V&beta;3 integrin ligand as tumor homing moiety and the monomethyl auristatin E (MMAE) as cytotoxic payload led to a 4-fold more potent anti-tumoral effect of the final conjugate on different cancer cell lines. In addition, the synthesized conjugate resulted to be significantly more potent than the free MMAE when tested following the kiss-and-run protocol, and the relative potency were clearly consistent with the expression of the &alpha;V&beta;3 integrin receptor in the considered cancer cell lines. In vitro enzymatic cleavage tests showed that the GPLG-PABC linker is cleaved by lysosomal enzymes, and that the released drug is observable already after 15 min of incubation. Although additional data are needed to fully characterize the releasing capacity of GPLG-PABC linker, our findings are of therapeutic significance since we are introducing an alternative to other well-established enzymatically sensitive peptide sequences that might be used in the future for generating more efficient and less toxic drug delivery systems."
REF00622	PDC_02125	Melanoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	70.4 &plusmn; 7.1 nM	nM	.	.	.	.	Melanoma	SK-MEL-202 cell	.	.	72 h	.	MTT assay	"In a first instance we performed an in vitro antiproliferative assay in which the different cell lines were incubated with different concentrations of the conjugate 2 for 72 h. As reported in Figure 3, 2 showed a potent antitumor activity in a low nanomolar range, from 3.7 to 70.4 nM depending on the cancer cell line, whereas the treatment with the free drug MMAE led to an antitumor activity of 0.03 nM for SK-OV-3 and of 0.23 nM for U87MG, and in very low nanomolar range on SK-MEL-28 cell line. Interestingly, the relative potency (RP) of the conjugate, normalized with respect to MMAE (i.e., the ratio of the IC50 values of 2 vs. MMAE) in U87MG cancer cell line after 72 h was much lower than the one observed with the previously reported cyclo[DKP-isoDGR]-PEG4-VA-PABC-MMAE (33-fold loss of potency vs. 151-fold loss of potency, respectively) bearing the VA linker. This data could suggest a positive effect of the GPLG cleavable linker on the release of the MMAE. Furthermore, a drop of potency between the free drug and the conjugate can be noticed in A549 from the RP value, where the integrin receptor level is significantly lower than in the other cancer cell lines. To better explore the targeting ability of the conjugate 2 towards different level of integrin expression, we decided to further evaluate the antiproliferative activity of the GPLG-conjugate by changing the incubation time."	"Here, we show that the replacement of the Val-Ala-p-aminobenzyloxycarbamate linker with the Gly-Pro-Leu-Gly-p-aminobenzyloxycarbamate (GPLG-PABC) sequence as enzymatically cleavable linker in the SMDC bearing the cyclo[DKP-isoDGR] &alpha;V&beta;3 integrin ligand as tumor homing moiety and the monomethyl auristatin E (MMAE) as cytotoxic payload led to a 4-fold more potent anti-tumoral effect of the final conjugate on different cancer cell lines. In addition, the synthesized conjugate resulted to be significantly more potent than the free MMAE when tested following the kiss-and-run protocol, and the relative potency were clearly consistent with the expression of the &alpha;V&beta;3 integrin receptor in the considered cancer cell lines. In vitro enzymatic cleavage tests showed that the GPLG-PABC linker is cleaved by lysosomal enzymes, and that the released drug is observable already after 15 min of incubation. Although additional data are needed to fully characterize the releasing capacity of GPLG-PABC linker, our findings are of therapeutic significance since we are introducing an alternative to other well-established enzymatically sensitive peptide sequences that might be used in the future for generating more efficient and less toxic drug delivery systems."
REF00622	PDC_02125	Ovarian serous cystadenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	3.7 &plusmn; 0.3 nM	nM	.	.	.	.	Ovarian serous cystadenocarcinoma	SK-OV-3 cell	.	.	72 h	.	MTT assay	"In a first instance we performed an in vitro antiproliferative assay in which the different cell lines were incubated with different concentrations of the conjugate 2 for 72 h. As reported in Figure 3, 2 showed a potent antitumor activity in a low nanomolar range, from 3.7 to 70.4 nM depending on the cancer cell line, whereas the treatment with the free drug MMAE led to an antitumor activity of 0.03 nM for SK-OV-3 and of 0.23 nM for U87MG, and in very low nanomolar range on SK-MEL-28 cell line. Interestingly, the relative potency (RP) of the conjugate, normalized with respect to MMAE (i.e., the ratio of the IC50 values of 2 vs. MMAE) in U87MG cancer cell line after 72 h was much lower than the one observed with the previously reported cyclo[DKP-isoDGR]-PEG4-VA-PABC-MMAE (33-fold loss of potency vs. 151-fold loss of potency, respectively) bearing the VA linker. This data could suggest a positive effect of the GPLG cleavable linker on the release of the MMAE. Furthermore, a drop of potency between the free drug and the conjugate can be noticed in A549 from the RP value, where the integrin receptor level is significantly lower than in the other cancer cell lines. To better explore the targeting ability of the conjugate 2 towards different level of integrin expression, we decided to further evaluate the antiproliferative activity of the GPLG-conjugate by changing the incubation time."	"Here, we show that the replacement of the Val-Ala-p-aminobenzyloxycarbamate linker with the Gly-Pro-Leu-Gly-p-aminobenzyloxycarbamate (GPLG-PABC) sequence as enzymatically cleavable linker in the SMDC bearing the cyclo[DKP-isoDGR] &alpha;V&beta;3 integrin ligand as tumor homing moiety and the monomethyl auristatin E (MMAE) as cytotoxic payload led to a 4-fold more potent anti-tumoral effect of the final conjugate on different cancer cell lines. In addition, the synthesized conjugate resulted to be significantly more potent than the free MMAE when tested following the kiss-and-run protocol, and the relative potency were clearly consistent with the expression of the &alpha;V&beta;3 integrin receptor in the considered cancer cell lines. In vitro enzymatic cleavage tests showed that the GPLG-PABC linker is cleaved by lysosomal enzymes, and that the released drug is observable already after 15 min of incubation. Although additional data are needed to fully characterize the releasing capacity of GPLG-PABC linker, our findings are of therapeutic significance since we are introducing an alternative to other well-established enzymatically sensitive peptide sequences that might be used in the future for generating more efficient and less toxic drug delivery systems."
REF00622	PDC_02125	Lung adenocarcinoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	20.8 &plusmn; 1.8 nM	nM	.	.	.	.	Lung adenocarcinoma	A-549 cell	.	.	72 h	.	MTT assay	"In a first instance we performed an in vitro antiproliferative assay in which the different cell lines were incubated with different concentrations of the conjugate 2 for 72 h. As reported in Figure 3, 2 showed a potent antitumor activity in a low nanomolar range, from 3.7 to 70.4 nM depending on the cancer cell line, whereas the treatment with the free drug MMAE led to an antitumor activity of 0.03 nM for SK-OV-3 and of 0.23 nM for U87MG, and in very low nanomolar range on SK-MEL-28 cell line. Interestingly, the relative potency (RP) of the conjugate, normalized with respect to MMAE (i.e., the ratio of the IC50 values of 2 vs. MMAE) in U87MG cancer cell line after 72 h was much lower than the one observed with the previously reported cyclo[DKP-isoDGR]-PEG4-VA-PABC-MMAE (33-fold loss of potency vs. 151-fold loss of potency, respectively) bearing the VA linker. This data could suggest a positive effect of the GPLG cleavable linker on the release of the MMAE. Furthermore, a drop of potency between the free drug and the conjugate can be noticed in A549 from the RP value, where the integrin receptor level is significantly lower than in the other cancer cell lines. To better explore the targeting ability of the conjugate 2 towards different level of integrin expression, we decided to further evaluate the antiproliferative activity of the GPLG-conjugate by changing the incubation time."	"Here, we show that the replacement of the Val-Ala-p-aminobenzyloxycarbamate linker with the Gly-Pro-Leu-Gly-p-aminobenzyloxycarbamate (GPLG-PABC) sequence as enzymatically cleavable linker in the SMDC bearing the cyclo[DKP-isoDGR] &alpha;V&beta;3 integrin ligand as tumor homing moiety and the monomethyl auristatin E (MMAE) as cytotoxic payload led to a 4-fold more potent anti-tumoral effect of the final conjugate on different cancer cell lines. In addition, the synthesized conjugate resulted to be significantly more potent than the free MMAE when tested following the kiss-and-run protocol, and the relative potency were clearly consistent with the expression of the &alpha;V&beta;3 integrin receptor in the considered cancer cell lines. In vitro enzymatic cleavage tests showed that the GPLG-PABC linker is cleaved by lysosomal enzymes, and that the released drug is observable already after 15 min of incubation. Although additional data are needed to fully characterize the releasing capacity of GPLG-PABC linker, our findings are of therapeutic significance since we are introducing an alternative to other well-established enzymatically sensitive peptide sequences that might be used in the future for generating more efficient and less toxic drug delivery systems."
REF00618	PDC_02127	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	0.9 &plusmn; 0.07 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"The cytotoxicity experiment was done by incubating the cells with different treatments for 48 h. The results show that conjugate 1 is quite similar to free Dox for toxicity to MCF-7 and MDA-MB-435 cancer cells. In contrast, conjugate 2 was ?20 times less cytotoxic to breast cancerous cells compared to free Dox. This could be attributed to the stability of the amide conjugate 2 inside the cells. Furthermore, the cytotoxicity of conjugate 1 in doxorubicin-resistant cell model MDA-MB-435-MDR (IC50 = 5.4 &mu;M) is 4 times more than free Dox (IC50 = 22 &mu;M). In normal cells (HUVEC and MCF-10A) the two conjugates were 3540 times less toxic compared to breast cancer cells, whereas free Dox was equally cytotoxic (equal IC50) to breast cancer cells and noncancerous cells. Overall these results provide clear evidence that of the two conjugates (conjugate 1 and 2), conjugate 1 has optimal characteristics for specific Dox targeting to breast cancer cells."	"Here we report the design and synthesis of two new peptide-Dox conjugates (1 and 2) for the specific delivery of Dox to the breast cancer cells and the ability to overcome P-glycoprotein multidrug resistance pathway in both drug-sensitive and drug-resistant cancer cells. Peptide-Dox conjugates were evaluated for DOX release in human serum, intracellular delivery compared to free Dox in three cancerous cells (MCF-7, MDA-MB-435, and MDA-MB-435-MDR) and two noncancerous cell lines (HUVEC and MCF-10A), and cytotoxicity compared to free Dox. Results show that both the peptide-Dox conjugates (1 and 2) enter sensitive and resistant cell lines with minimal uptake in normal cells compared to free Dox. Cellular uptake is most likely mediated by a cell specific receptor, as the amount of internalized conjugates significantly decreased in the presence of excess free peptide. Importantly, conjugate 1 is equally cytotoxic as Dox in drug sensitive breast cancer cells and 4 times more potent than free Dox in Dox resistant cell line. Overall, the peptide-Dox ester conjugate 1 showed better breast targeting efficacy than the amide conjugate 2, most likely due to the slow release of Dox from the stable amide linkage."
REF00618	PDC_02127	Amelanotic melanoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	1.5 &plusmn; 0.09 &mu;M	&mu;M	.	.	.	.	Amelanotic melanoma	MDA-MB-435 cell	.	.	48 h	.	MTT assay	"The cytotoxicity experiment was done by incubating the cells with different treatments for 48 h. The results show that conjugate 1 is quite similar to free Dox for toxicity to MCF-7 and MDA-MB-435 cancer cells. In contrast, conjugate 2 was ?20 times less cytotoxic to breast cancerous cells compared to free Dox. This could be attributed to the stability of the amide conjugate 2 inside the cells. Furthermore, the cytotoxicity of conjugate 1 in doxorubicin-resistant cell model MDA-MB-435-MDR (IC50 = 5.4 &mu;M) is 4 times more than free Dox (IC50 = 22 &mu;M). In normal cells (HUVEC and MCF-10A) the two conjugates were 3540 times less toxic compared to breast cancer cells, whereas free Dox was equally cytotoxic (equal IC50) to breast cancer cells and noncancerous cells. Overall these results provide clear evidence that of the two conjugates (conjugate 1 and 2), conjugate 1 has optimal characteristics for specific Dox targeting to breast cancer cells."	"Here we report the design and synthesis of two new peptide-Dox conjugates (1 and 2) for the specific delivery of Dox to the breast cancer cells and the ability to overcome P-glycoprotein multidrug resistance pathway in both drug-sensitive and drug-resistant cancer cells. Peptide-Dox conjugates were evaluated for DOX release in human serum, intracellular delivery compared to free Dox in three cancerous cells (MCF-7, MDA-MB-435, and MDA-MB-435-MDR) and two noncancerous cell lines (HUVEC and MCF-10A), and cytotoxicity compared to free Dox. Results show that both the peptide-Dox conjugates (1 and 2) enter sensitive and resistant cell lines with minimal uptake in normal cells compared to free Dox. Cellular uptake is most likely mediated by a cell specific receptor, as the amount of internalized conjugates significantly decreased in the presence of excess free peptide. Importantly, conjugate 1 is equally cytotoxic as Dox in drug sensitive breast cancer cells and 4 times more potent than free Dox in Dox resistant cell line. Overall, the peptide-Dox ester conjugate 1 showed better breast targeting efficacy than the amide conjugate 2, most likely due to the slow release of Dox from the stable amide linkage."
REF00618	PDC_02127	Amelanotic melanoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	5.4 &plusmn; 0.62 &mu;M	&mu;M	.	.	.	.	Amelanotic melanoma	MDA-MB-435 cell	.	.	48 h	.	MTT assay	"The cytotoxicity experiment was done by incubating the cells with different treatments for 48 h. The results show that conjugate 1 is quite similar to free Dox for toxicity to MCF-7 and MDA-MB-435 cancer cells. In contrast, conjugate 2 was ?20 times less cytotoxic to breast cancerous cells compared to free Dox. This could be attributed to the stability of the amide conjugate 2 inside the cells. Furthermore, the cytotoxicity of conjugate 1 in doxorubicin-resistant cell model MDA-MB-435-MDR (IC50 = 5.4 &mu;M) is 4 times more than free Dox (IC50 = 22 &mu;M). In normal cells (HUVEC and MCF-10A) the two conjugates were 3540 times less toxic compared to breast cancer cells, whereas free Dox was equally cytotoxic (equal IC50) to breast cancer cells and noncancerous cells. Overall these results provide clear evidence that of the two conjugates (conjugate 1 and 2), conjugate 1 has optimal characteristics for specific Dox targeting to breast cancer cells."	"Here we report the design and synthesis of two new peptide-Dox conjugates (1 and 2) for the specific delivery of Dox to the breast cancer cells and the ability to overcome P-glycoprotein multidrug resistance pathway in both drug-sensitive and drug-resistant cancer cells. Peptide-Dox conjugates were evaluated for DOX release in human serum, intracellular delivery compared to free Dox in three cancerous cells (MCF-7, MDA-MB-435, and MDA-MB-435-MDR) and two noncancerous cell lines (HUVEC and MCF-10A), and cytotoxicity compared to free Dox. Results show that both the peptide-Dox conjugates (1 and 2) enter sensitive and resistant cell lines with minimal uptake in normal cells compared to free Dox. Cellular uptake is most likely mediated by a cell specific receptor, as the amount of internalized conjugates significantly decreased in the presence of excess free peptide. Importantly, conjugate 1 is equally cytotoxic as Dox in drug sensitive breast cancer cells and 4 times more potent than free Dox in Dox resistant cell line. Overall, the peptide-Dox ester conjugate 1 showed better breast targeting efficacy than the amide conjugate 2, most likely due to the slow release of Dox from the stable amide linkage."
REF00618	PDC_02127	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	35.1 &plusmn; 2.2 &mu;M	&mu;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	MTT assay	"The cytotoxicity experiment was done by incubating the cells with different treatments for 48 h. The results show that conjugate 1 is quite similar to free Dox for toxicity to MCF-7 and MDA-MB-435 cancer cells. In contrast, conjugate 2 was ?20 times less cytotoxic to breast cancerous cells compared to free Dox. This could be attributed to the stability of the amide conjugate 2 inside the cells. Furthermore, the cytotoxicity of conjugate 1 in doxorubicin-resistant cell model MDA-MB-435-MDR (IC50 = 5.4 &mu;M) is 4 times more than free Dox (IC50 = 22 &mu;M). In normal cells (HUVEC and MCF-10A) the two conjugates were 3540 times less toxic compared to breast cancer cells, whereas free Dox was equally cytotoxic (equal IC50) to breast cancer cells and noncancerous cells. Overall these results provide clear evidence that of the two conjugates (conjugate 1 and 2), conjugate 1 has optimal characteristics for specific Dox targeting to breast cancer cells."	"Here we report the design and synthesis of two new peptide-Dox conjugates (1 and 2) for the specific delivery of Dox to the breast cancer cells and the ability to overcome P-glycoprotein multidrug resistance pathway in both drug-sensitive and drug-resistant cancer cells. Peptide-Dox conjugates were evaluated for DOX release in human serum, intracellular delivery compared to free Dox in three cancerous cells (MCF-7, MDA-MB-435, and MDA-MB-435-MDR) and two noncancerous cell lines (HUVEC and MCF-10A), and cytotoxicity compared to free Dox. Results show that both the peptide-Dox conjugates (1 and 2) enter sensitive and resistant cell lines with minimal uptake in normal cells compared to free Dox. Cellular uptake is most likely mediated by a cell specific receptor, as the amount of internalized conjugates significantly decreased in the presence of excess free peptide. Importantly, conjugate 1 is equally cytotoxic as Dox in drug sensitive breast cancer cells and 4 times more potent than free Dox in Dox resistant cell line. Overall, the peptide-Dox ester conjugate 1 showed better breast targeting efficacy than the amide conjugate 2, most likely due to the slow release of Dox from the stable amide linkage."
REF00618	PDC_02127	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	42.3 &plusmn; 2.4 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	.	48 h	.	MTT assay	"The cytotoxicity experiment was done by incubating the cells with different treatments for 48 h. The results show that conjugate 1 is quite similar to free Dox for toxicity to MCF-7 and MDA-MB-435 cancer cells. In contrast, conjugate 2 was ?20 times less cytotoxic to breast cancerous cells compared to free Dox. This could be attributed to the stability of the amide conjugate 2 inside the cells. Furthermore, the cytotoxicity of conjugate 1 in doxorubicin-resistant cell model MDA-MB-435-MDR (IC50 = 5.4 &mu;M) is 4 times more than free Dox (IC50 = 22 &mu;M). In normal cells (HUVEC and MCF-10A) the two conjugates were 3540 times less toxic compared to breast cancer cells, whereas free Dox was equally cytotoxic (equal IC50) to breast cancer cells and noncancerous cells. Overall these results provide clear evidence that of the two conjugates (conjugate 1 and 2), conjugate 1 has optimal characteristics for specific Dox targeting to breast cancer cells."	"Here we report the design and synthesis of two new peptide-Dox conjugates (1 and 2) for the specific delivery of Dox to the breast cancer cells and the ability to overcome P-glycoprotein multidrug resistance pathway in both drug-sensitive and drug-resistant cancer cells. Peptide-Dox conjugates were evaluated for DOX release in human serum, intracellular delivery compared to free Dox in three cancerous cells (MCF-7, MDA-MB-435, and MDA-MB-435-MDR) and two noncancerous cell lines (HUVEC and MCF-10A), and cytotoxicity compared to free Dox. Results show that both the peptide-Dox conjugates (1 and 2) enter sensitive and resistant cell lines with minimal uptake in normal cells compared to free Dox. Cellular uptake is most likely mediated by a cell specific receptor, as the amount of internalized conjugates significantly decreased in the presence of excess free peptide. Importantly, conjugate 1 is equally cytotoxic as Dox in drug sensitive breast cancer cells and 4 times more potent than free Dox in Dox resistant cell line. Overall, the peptide-Dox ester conjugate 1 showed better breast targeting efficacy than the amide conjugate 2, most likely due to the slow release of Dox from the stable amide linkage."
REF00618	PDC_02128	Breast cancer	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	191 &plusmn; 2.8 &mu;M	&mu;M	.	.	.	.	Invasive breast carcinoma	MCF-7 cell	.	.	48 h	.	MTT assay	"The cytotoxicity experiment was done by incubating the cells with different treatments for 48 h. The results show that conjugate 1 is quite similar to free Dox for toxicity to MCF-7 and MDA-MB-435 cancer cells. In contrast, conjugate 2 was ?20 times less cytotoxic to breast cancerous cells compared to free Dox. This could be attributed to the stability of the amide conjugate 2 inside the cells. Furthermore, the cytotoxicity of conjugate 1 in doxorubicin-resistant cell model MDA-MB-435-MDR (IC50 = 5.4 &mu;M) is 4 times more than free Dox (IC50 = 22 &mu;M). In normal cells (HUVEC and MCF-10A) the two conjugates were 3540 times less toxic compared to breast cancer cells, whereas free Dox was equally cytotoxic (equal IC50) to breast cancer cells and noncancerous cells. Overall these results provide clear evidence that of the two conjugates (conjugate 1 and 2), conjugate 1 has optimal characteristics for specific Dox targeting to breast cancer cells."	"Here we report the design and synthesis of two new peptide-Dox conjugates (1 and 2) for the specific delivery of Dox to the breast cancer cells and the ability to overcome P-glycoprotein multidrug resistance pathway in both drug-sensitive and drug-resistant cancer cells. Peptide-Dox conjugates were evaluated for DOX release in human serum, intracellular delivery compared to free Dox in three cancerous cells (MCF-7, MDA-MB-435, and MDA-MB-435-MDR) and two noncancerous cell lines (HUVEC and MCF-10A), and cytotoxicity compared to free Dox. Results show that both the peptide-Dox conjugates (1 and 2) enter sensitive and resistant cell lines with minimal uptake in normal cells compared to free Dox. Cellular uptake is most likely mediated by a cell specific receptor, as the amount of internalized conjugates significantly decreased in the presence of excess free peptide. Importantly, conjugate 1 is equally cytotoxic as Dox in drug sensitive breast cancer cells and 4 times more potent than free Dox in Dox resistant cell line. Overall, the peptide-Dox ester conjugate 1 showed better breast targeting efficacy than the amide conjugate 2, most likely due to the slow release of Dox from the stable amide linkage."
REF00618	PDC_02128	Amelanotic melanoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	18.6 &plusmn; 2.5 &mu;M	&mu;M	.	.	.	.	Amelanotic melanoma	MDA-MB-435 cell	.	.	48 h	.	MTT assay	"The cytotoxicity experiment was done by incubating the cells with different treatments for 48 h. The results show that conjugate 1 is quite similar to free Dox for toxicity to MCF-7 and MDA-MB-435 cancer cells. In contrast, conjugate 2 was ?20 times less cytotoxic to breast cancerous cells compared to free Dox. This could be attributed to the stability of the amide conjugate 2 inside the cells. Furthermore, the cytotoxicity of conjugate 1 in doxorubicin-resistant cell model MDA-MB-435-MDR (IC50 = 5.4 &mu;M) is 4 times more than free Dox (IC50 = 22 &mu;M). In normal cells (HUVEC and MCF-10A) the two conjugates were 3540 times less toxic compared to breast cancer cells, whereas free Dox was equally cytotoxic (equal IC50) to breast cancer cells and noncancerous cells. Overall these results provide clear evidence that of the two conjugates (conjugate 1 and 2), conjugate 1 has optimal characteristics for specific Dox targeting to breast cancer cells."	"Here we report the design and synthesis of two new peptide-Dox conjugates (1 and 2) for the specific delivery of Dox to the breast cancer cells and the ability to overcome P-glycoprotein multidrug resistance pathway in both drug-sensitive and drug-resistant cancer cells. Peptide-Dox conjugates were evaluated for DOX release in human serum, intracellular delivery compared to free Dox in three cancerous cells (MCF-7, MDA-MB-435, and MDA-MB-435-MDR) and two noncancerous cell lines (HUVEC and MCF-10A), and cytotoxicity compared to free Dox. Results show that both the peptide-Dox conjugates (1 and 2) enter sensitive and resistant cell lines with minimal uptake in normal cells compared to free Dox. Cellular uptake is most likely mediated by a cell specific receptor, as the amount of internalized conjugates significantly decreased in the presence of excess free peptide. Importantly, conjugate 1 is equally cytotoxic as Dox in drug sensitive breast cancer cells and 4 times more potent than free Dox in Dox resistant cell line. Overall, the peptide-Dox ester conjugate 1 showed better breast targeting efficacy than the amide conjugate 2, most likely due to the slow release of Dox from the stable amide linkage."
REF00618	PDC_02128	Amelanotic melanoma	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	19.7 &plusmn; 3.1 &mu;M	&mu;M	.	.	.	.	Amelanotic melanoma	MDA-MB-435 cell	.	.	48 h	.	MTT assay	"The cytotoxicity experiment was done by incubating the cells with different treatments for 48 h. The results show that conjugate 1 is quite similar to free Dox for toxicity to MCF-7 and MDA-MB-435 cancer cells. In contrast, conjugate 2 was ?20 times less cytotoxic to breast cancerous cells compared to free Dox. This could be attributed to the stability of the amide conjugate 2 inside the cells. Furthermore, the cytotoxicity of conjugate 1 in doxorubicin-resistant cell model MDA-MB-435-MDR (IC50 = 5.4 &mu;M) is 4 times more than free Dox (IC50 = 22 &mu;M). In normal cells (HUVEC and MCF-10A) the two conjugates were 3540 times less toxic compared to breast cancer cells, whereas free Dox was equally cytotoxic (equal IC50) to breast cancer cells and noncancerous cells. Overall these results provide clear evidence that of the two conjugates (conjugate 1 and 2), conjugate 1 has optimal characteristics for specific Dox targeting to breast cancer cells."	"Here we report the design and synthesis of two new peptide-Dox conjugates (1 and 2) for the specific delivery of Dox to the breast cancer cells and the ability to overcome P-glycoprotein multidrug resistance pathway in both drug-sensitive and drug-resistant cancer cells. Peptide-Dox conjugates were evaluated for DOX release in human serum, intracellular delivery compared to free Dox in three cancerous cells (MCF-7, MDA-MB-435, and MDA-MB-435-MDR) and two noncancerous cell lines (HUVEC and MCF-10A), and cytotoxicity compared to free Dox. Results show that both the peptide-Dox conjugates (1 and 2) enter sensitive and resistant cell lines with minimal uptake in normal cells compared to free Dox. Cellular uptake is most likely mediated by a cell specific receptor, as the amount of internalized conjugates significantly decreased in the presence of excess free peptide. Importantly, conjugate 1 is equally cytotoxic as Dox in drug sensitive breast cancer cells and 4 times more potent than free Dox in Dox resistant cell line. Overall, the peptide-Dox ester conjugate 1 showed better breast targeting efficacy than the amide conjugate 2, most likely due to the slow release of Dox from the stable amide linkage."
REF00618	PDC_02128	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	40.5 &plusmn; 4.3 &mu;M	&mu;M	.	.	.	.	Normal	MCF-10A cell	.	.	48 h	.	MTT assay	"The cytotoxicity experiment was done by incubating the cells with different treatments for 48 h. The results show that conjugate 1 is quite similar to free Dox for toxicity to MCF-7 and MDA-MB-435 cancer cells. In contrast, conjugate 2 was ?20 times less cytotoxic to breast cancerous cells compared to free Dox. This could be attributed to the stability of the amide conjugate 2 inside the cells. Furthermore, the cytotoxicity of conjugate 1 in doxorubicin-resistant cell model MDA-MB-435-MDR (IC50 = 5.4 &mu;M) is 4 times more than free Dox (IC50 = 22 &mu;M). In normal cells (HUVEC and MCF-10A) the two conjugates were 3540 times less toxic compared to breast cancer cells, whereas free Dox was equally cytotoxic (equal IC50) to breast cancer cells and noncancerous cells. Overall these results provide clear evidence that of the two conjugates (conjugate 1 and 2), conjugate 1 has optimal characteristics for specific Dox targeting to breast cancer cells."	"Here we report the design and synthesis of two new peptide-Dox conjugates (1 and 2) for the specific delivery of Dox to the breast cancer cells and the ability to overcome P-glycoprotein multidrug resistance pathway in both drug-sensitive and drug-resistant cancer cells. Peptide-Dox conjugates were evaluated for DOX release in human serum, intracellular delivery compared to free Dox in three cancerous cells (MCF-7, MDA-MB-435, and MDA-MB-435-MDR) and two noncancerous cell lines (HUVEC and MCF-10A), and cytotoxicity compared to free Dox. Results show that both the peptide-Dox conjugates (1 and 2) enter sensitive and resistant cell lines with minimal uptake in normal cells compared to free Dox. Cellular uptake is most likely mediated by a cell specific receptor, as the amount of internalized conjugates significantly decreased in the presence of excess free peptide. Importantly, conjugate 1 is equally cytotoxic as Dox in drug sensitive breast cancer cells and 4 times more potent than free Dox in Dox resistant cell line. Overall, the peptide-Dox ester conjugate 1 showed better breast targeting efficacy than the amide conjugate 2, most likely due to the slow release of Dox from the stable amide linkage."
REF00618	PDC_02128	Solid tumor	.	Revealed Based on the Cell Line Data	.	Half maximal inhibitory concentration (IC50)	50.9 &plusmn; 3.2 &mu;M	&mu;M	.	.	.	.	Normal	Human umbilical vein endothelial cell	.	.	48 h	.	MTT assay	"The cytotoxicity experiment was done by incubating the cells with different treatments for 48 h. The results show that conjugate 1 is quite similar to free Dox for toxicity to MCF-7 and MDA-MB-435 cancer cells. In contrast, conjugate 2 was ?20 times less cytotoxic to breast cancerous cells compared to free Dox. This could be attributed to the stability of the amide conjugate 2 inside the cells. Furthermore, the cytotoxicity of conjugate 1 in doxorubicin-resistant cell model MDA-MB-435-MDR (IC50 = 5.4 &mu;M) is 4 times more than free Dox (IC50 = 22 &mu;M). In normal cells (HUVEC and MCF-10A) the two conjugates were 3540 times less toxic compared to breast cancer cells, whereas free Dox was equally cytotoxic (equal IC50) to breast cancer cells and noncancerous cells. Overall these results provide clear evidence that of the two conjugates (conjugate 1 and 2), conjugate 1 has optimal characteristics for specific Dox targeting to breast cancer cells."	"Here we report the design and synthesis of two new peptide-Dox conjugates (1 and 2) for the specific delivery of Dox to the breast cancer cells and the ability to overcome P-glycoprotein multidrug resistance pathway in both drug-sensitive and drug-resistant cancer cells. Peptide-Dox conjugates were evaluated for DOX release in human serum, intracellular delivery compared to free Dox in three cancerous cells (MCF-7, MDA-MB-435, and MDA-MB-435-MDR) and two noncancerous cell lines (HUVEC and MCF-10A), and cytotoxicity compared to free Dox. Results show that both the peptide-Dox conjugates (1 and 2) enter sensitive and resistant cell lines with minimal uptake in normal cells compared to free Dox. Cellular uptake is most likely mediated by a cell specific receptor, as the amount of internalized conjugates significantly decreased in the presence of excess free peptide. Importantly, conjugate 1 is equally cytotoxic as Dox in drug sensitive breast cancer cells and 4 times more potent than free Dox in Dox resistant cell line. Overall, the peptide-Dox ester conjugate 1 showed better breast targeting efficacy than the amide conjugate 2, most likely due to the slow release of Dox from the stable amide linkage."
REF00620	PDC_02131	Triple-negative breast cancer	.	Revealed Based on the Cell Line Data	.	Cell viability	10%	%	.	.	.	.	Breast adenocarcinoma	MDA-MB-231 cell	.	.	24 h	.	MTT assay	"The internalization of nanoparticles in cancer cells is the foremost step in PDT. Targeting ligand decoration and reducing nanoparticle size have been intensively explored to enhance the intracellular uptake of nanoparticles. Therefore, the PPC nanoparticles were designed to offer the appropriate size and targeting ability for delivery of Ce6 to tumor tissues via active and passive targeting mechanisms. The cellular internalization of free Ce6 and PPC into various cancer cells, i.e., MDA-MB-231, MKN-28, and HeLa, was assessed by fluorescence-activated cell sorting (FACS) analysis using a flow cytometer. When compared with free Ce6, the higher cellular internalization of PPC was observed in all cancer cells tested. In particular, the fluorescence intensity due to the intracellular uptake of PPC in MDA-MB-231 cells increased more dramatically than in the other cancer cells."	"Polyhedral oligomeric silsesquioxane (POSS) molecules have a distinct nanostructure, consisting of an inner inorganic cage core of silicon and oxygen atoms and an outer shell of organic functional groups. The unique structure of POSS molecules containing reactive functionalities and their superior biocompatibility make them suitable drug-delivery carriers. In the present study, we prepared p 18-4/chlorin e6 (Ce6)-conjugated POSS (PPC) nanoparticles for improving the targeting ability of Ce6 to breast cancer cells. To fabricate PPC nanoparticles, p 18-4 was first covalently conjugated on OctaMaleamicacid POSS (OM-POSS), and subsequently, amino-terminated Ce6 was introduced. To verify the availability of the PPC nanoparticles for cancer therapy, their physicochemical properties, including morphology, chemical structure, and particle size, were systematically characterized. The cellular uptake, phototoxicity, and targeting ability of the PPC nanoparticles were assessed using a human breast cancer cell line MDA-MB-231. In addition, PPC nanoparticles was injected intravenously into tumor-bearing mice to evaluate in vivo biodistribution and PDT efficacy."
REF00316	PDC_00358	Obesity	DIO mice	Obtained from the Model Organism Data	.	Vehicle-corrected weight loss rate	23.20%	%	.	.	.	.	.	.	1.9 h	.	Once a day for 14 days	100 nmol kg<sup>-1</sup>	"Over a 14-day treatment period, GLP-1-MK-801 synergistically lowered body weight compared with the dose-matched monotherapies and produced a vehicle-corrected weight loss of 23.2%."	.	"Treatment with GLP-1-inactive MK-801 produced no additional weight loss efficacy relative to GLP-1 monotherapy (Fig. 2g-i), indicating that the pronounced weight loss induced by GLP-1-MK-801 is driven by concerted and site-directed pharmacological GLP-1 receptor agonism and NMDA receptor antagonism."
REF00316	PDC_00358	Obesity	DIO mice	Obtained from the Model Organism Data	.	Fat mass reduction rate	45%	%	.	.	.	.	.	.	1.9 h	.	Once a day for 14 days	100 nmol kg<sup>-1</sup>	"GLP-1-MK-801 produced a vehicle-corrected reduction in body fat mass of 45%, accompanied by an 8% loss in lean mass."	.	"Treatment with GLP-1-inactive MK-801 produced no additional weight loss efficacy relative to GLP-1 monotherapy (Fig. 2g-i), indicating that the pronounced weight loss induced by GLP-1-MK-801 is driven by concerted and site-directed pharmacological GLP-1 receptor agonism and NMDA receptor antagonism."
REF00316	PDC_00358	Obesity	DIO mice	Obtained from the Model Organism Data	.	Lean mass rate	8%	%	.	.	.	.	.	.	1.9 h	.	Once a day for 14 days	100 nmol kg<sup>-1</sup>	"GLP-1-MK-801 produced a vehicle-corrected reduction in body fat mass of 45%, accompanied by an 8% loss in lean mass."	.	"Treatment with GLP-1-inactive MK-801 produced no additional weight loss efficacy relative to GLP-1 monotherapy (Fig. 2g-i), indicating that the pronounced weight loss induced by GLP-1-MK-801 is driven by concerted and site-directed pharmacological GLP-1 receptor agonism and NMDA receptor antagonism."
REF00316	PDC_00358	Obesity	Mc4r-KO mice	Obtained from the Model Organism Data	.	Vehicle-corrected weight loss rate	15.20%	%	.	.	.	.	.	.	1.9 h	.	Once a day for 9 days	100 nmol kg<sup>-1</sup>	"We observed a pronounced vehicle-corrected weight loss of 15.2% in the group treated with GLP-1-MK-801 compared with 3.5% in the group treated with the parent GLP-1 analogue after 9days of treatment, underscoring that the weight-lowering efficacy of the conjugate is intact in the absence of functional MC4R signalling (Fig. 3l,m)."	.	"Treatment with GLP-1-inactive MK-801 produced no additional weight loss efficacy relative to GLP-1 monotherapy (Fig. 2g-i), indicating that the pronounced weight loss induced by GLP-1-MK-801 is driven by concerted and site-directed pharmacological GLP-1 receptor agonism and NMDA receptor antagonism."
REF00316	PDC_00358	Obesity	High-fat high-sucrose-fed mice	Obtained from the Model Organism Data	.	Vehicle-corrected weight loss rate	9.50%	%	.	.	.	.	.	.	1.9 h	.	1 dose	0.22 nmol	This study revealed a superior vehicle-corrected weight loss of 9.5% in response to the GLP-1-MK-801 infusion relative to a weight loss of 4.5% after semaglutide infusion (Fig. 4b). 	.	"Treatment with GLP-1-inactive MK-801 produced no additional weight loss efficacy relative to GLP-1 monotherapy (Fig. 2g-i), indicating that the pronounced weight loss induced by GLP-1-MK-801 is driven by concerted and site-directed pharmacological GLP-1 receptor agonism and NMDA receptor antagonism."
REF00197	PDC_00359	Ovarian cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	54 nM	nM	.	.	.	.	Ovarian clear cell adenocarcinoma	ES-2 cell	.	.	12 h	.	.	TH1904 IC50 value was 54 nM for the number of loops inhibition (Figure 5B).	"Overall, these results indicate that both conjugates alter cell migration in either TNBC or ovarian cancer cell models through a SORT1-dependent mechanism. The effects of TH1902 and TH1904 on cell migration further support the molecular rationale that inhibition of VM activity may result, in part, from the reduction of cancer cell invasive phenotype."
REF00149	PDC_00360	Solid tumor	Mice implanted with MT1-positive EBC-1 cells	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	100%	%	.	.	.	.	Lung squamous cell carcinoma	EBC-1 cell	.	.	12 days	10 mg/kg	Tumor volume detection	Treatment with BDCs containing the most labile linkers (BT17BDC17 orBT1718) showed rapid and complete tumour clearance (EBC-1 cells).	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00149	PDC_00360	Solid tumor	Mice implanted with MT1-positive HT-1080 cells	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	100%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	Twice a week for 12 days	10 mg/kg	Tumor volume detection	"Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 70 days."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00149	PDC_00360	Solid tumor	Mice implanted with MT1-positive HT-1080 cells	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	100%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	Twice a week for 12 days	3 mg/kg	Tumor volume detection	"Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 71 days."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00149	PDC_00360	Solid tumor	Mice implanted with MT1-positive HT-1080 cells	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	12.50%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	Twice a week for 12 days	1 mg/kg	Tumor volume detection	"Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 72 days."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00149	PDC_00360	Solid tumor	Mice implanted with MT1-positive HT-1080 cells	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	100%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	Three times a week for 12 days	10 mg/kg	Tumor volume detection	"Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 73 days."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00149	PDC_00360	Solid tumor	Mice implanted with MT1-positive HT-1080 cells	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	85.40%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	Three times a week for 12 days	3 mg/kg	Tumor volume detection	"Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 74 days."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00149	PDC_00360	Solid tumor	Mice implanted with MT1-positive HT-1080 cells	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	12.70%	%	.	.	.	.	Fibrosarcoma	HT-1080 cell	.	.	Three times a week for 12 days	1 mg/kg	Tumor volume detection	"Testing of BT1718 in different dosing regimes in an additional model (HT-1080 cells) also demonstrated excellent tumour regression, with 10mg/kg biw leading to complete tumour clearance in all 3 animals within 23 days and no re-growth out to 75 days."	"BT1718 is a novel first in class bicyclic targeting peptide that selectively binds MT1 MMP (MMP-14) and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicycle Toxin Conjugates have a low molecular weight compared to other conjugated toxin approaches, enabling rapid tumour penetration and a short systemic half-life (up to 40 minutes in non-human primates) potentially reducing toxicity. The target MT1-MMP (MT1) is a surface metalloproteinase involved in tissue remodelling through proteolysis of extracellular matrix components: Highly expressed in tumours with unmet medical need, such as triple negative breast cancer, non small cell lung cancer and ovarian cancer. Strong link with cell invasion and metastasis. High tumour MT1 expression is correlated with poor outcomes in multiple tumour types. High adjacent stromal expression and low expression in adult normal tissue."
REF00213	PDC_00361	Tumor	MDA-MB-231 xenografts	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	76.50%	%	.	.	.	.	.	.	.	.	35 days	10 mg/kg	Tumor volume detection	Combination treatment significantly inhibited tumor growth without significant toxicity in both mouse xenografts compared with CBX-12 and ceralasertib monotherapy without significant toxicity.	.
REF00213	PDC_00361	Tumor	MDA-MB-231 xenografts	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	95%	%	.	.	.	.	.	.	.	.	35 days	10 mg/kg with ceralasertib 25 mg/kg	Tumor volume detection	Combination treatment significantly inhibited tumor growth without significant toxicity in both mouse xenografts compared with CBX-12 and ceralasertib monotherapy without significant toxicity.	.
REF00213	PDC_00361	Tumor	HCT-116 xenografts	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	58.10%	%	.	.	.	.	.	.	.	.	23 days	5 mg/kg	Tumor volume detection	Combination treatment significantly inhibited tumor growth without significant toxicity in both mouse xenografts compared with CBX-12 and ceralasertib monotherapy without significant toxicity.	.
REF00213	PDC_00361	Tumor	HCT-116 xenografts	Discovered Using Cell Line-derived Xenograft Model	.	Tumor Growth Inhibition value (TGI)	81.40%	%	.	.	.	.	.	.	.	.	23 days	5 mg/kg with ceralasertib 25 mg/kg	Tumor volume detection	Combination treatment significantly inhibited tumor growth without significant toxicity in both mouse xenografts compared with CBX-12 and ceralasertib monotherapy without significant toxicity.	.
REF00213	PDC_00361	Tumor	MDA-MB-231 xenografts	Discovered Using Cell Line-derived Xenograft Model	.	Survival rate	75 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	42 days	10 mg/kg	.	Combination treatment significantly inhibited tumor growth without significant toxicity in both mouse xenografts compared with CBX-12 and ceralasertib monotherapy without significant toxicity.	.
REF00213	PDC_00361	Tumor	MDA-MB-231 xenografts	Discovered Using Cell Line-derived Xenograft Model	.	Survival rate	100 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	42 days	10 mg/kg with ceralasertib 25 mg/kg	.	Combination treatment significantly inhibited tumor growth without significant toxicity in both mouse xenografts compared with CBX-12 and ceralasertib monotherapy without significant toxicity.	.
REF00213	PDC_00361	Tumor	HCT-116 xenografts	Discovered Using Cell Line-derived Xenograft Model	.	Survival rate	60 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	45 days	5 mg/kg	.	Combination treatment significantly inhibited tumor growth without significant toxicity in both mouse xenografts compared with CBX-12 and ceralasertib monotherapy without significant toxicity.	.
REF00213	PDC_00361	Tumor	HCT-116 xenografts	Discovered Using Cell Line-derived Xenograft Model	.	Survival rate	100 mm<sup>3</sup>	mm<sup>3</sup>	.	.	.	.	.	.	.	.	45 days	5 mg/kg with ceralasertib 25 mg/kg	.	Combination treatment significantly inhibited tumor growth without significant toxicity in both mouse xenografts compared with CBX-12 and ceralasertib monotherapy without significant toxicity.	.
REF00317	PDC_00362	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.4 nM	nM	.	.	.	.	Prostate carcinoma	PC-3 cell	.	.	.	.	.	"In xenografted prostate cancer in mice, only 3 treatments over 12 days showed complete tumor regression. At the highest dose tested, there were no obvious symptoms of toxicity. After 60 days of observation, the tumor did not regrow."	.
REF00317	PDC_00362	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.3 nM	nM	.	.	.	.	Pancreatic ductal adenocarcinoma	BxPC-3 cell	.	.	.	.	.	"In xenografted prostate cancer in mice, only 3 treatments over 12 days showed complete tumor regression. At the highest dose tested, there were no obvious symptoms of toxicity. After 60 days of observation, the tumor did not regrow."	.
REF00317	PDC_00362	Pancreatic cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	2.6 nM	nM	.	.	.	.	Pancreatic ductal adenocarcinoma	MIA PaCa-2 cell	.	.	.	.	.	"In xenografted prostate cancer in mice, only 3 treatments over 12 days showed complete tumor regression. At the highest dose tested, there were no obvious symptoms of toxicity. After 60 days of observation, the tumor did not regrow."	.
REF00317	PDC_00362	Uterine corpus sarcoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half Maximal Inhibitory Concentration (IC50)	5.7 nM	nM	.	.	.	.	Uterine corpus sarcoma	MES-SA cell	.	.	.	.	.	"In xenografted prostate cancer in mice, only 3 treatments over 12 days showed complete tumor regression. At the highest dose tested, there were no obvious symptoms of toxicity. After 60 days of observation, the tumor did not regrow."	.
REF00317	PDC_00362	Prostate cancer	PC-3 mouse xenograft with prostate cancer	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	10%	%	.	.	.	.	.	.	.	.	54 days	0.3 mg/kg	Tumor volume detection	"In xenografted prostate cancer in mice, only 3 treatments over 12 days showed complete tumor regression. At the highest dose tested, there were no obvious symptoms of toxicity. After 60 days of observation, the tumor did not regrow."	.
REF00317	PDC_00362	Prostate cancer	PC-3 mouse xenograft with prostate cancer	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	75%	%	.	.	.	.	.	.	.	.	54 days	0.6 mg/kg	Tumor volume detection	"In xenografted prostate cancer in mice, only 3 treatments over 12 days showed complete tumor regression. At the highest dose tested, there were no obvious symptoms of toxicity. After 60 days of observation, the tumor did not regrow."	.
REF00317	PDC_00362	Prostate cancer	PC-3 mouse xenograft with prostate cancer	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	100%	%	.	.	.	.	.	.	.	.	54 days	1.2 mg/kg	Tumor volume detection	"In xenografted prostate cancer in mice, only 3 treatments over 12 days showed complete tumor regression. At the highest dose tested, there were no obvious symptoms of toxicity. After 60 days of observation, the tumor did not regrow."	.
REF00317	PDC_00362	Prostate cancer	PC-3 mouse xenograft with prostate cancer	Discovered Using Cell Line-derived Xenograft Model	High Expreesion	Tumor Growth Inhibition value (TGI)	100%	%	.	.	.	.	.	.	.	.	54 days	2.4 mg/kg	Tumor volume detection	"In xenografted prostate cancer in mice, only 3 treatments over 12 days showed complete tumor regression. At the highest dose tested, there were no obvious symptoms of toxicity. After 60 days of observation, the tumor did not regrow."	.
REF102528	PDC_02137	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	80	.	.	.	.	.	.	MCF-7 cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02136	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	180	.	.	.	.	.	.	MCF-7 cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02138	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	180	.	.	.	.	.	.	MCF-7 cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02135	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	505	.	.	.	.	.	.	MCF-7 cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02137	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	85	.	.	.	.	.	.	MDA-MB 231 cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02136	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	180	.	.	.	.	.	.	MDA-MB 231 cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02138	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	200	.	.	.	.	.	.	MDA-MB 231 cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02135	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	395	.	.	.	.	.	.	MDA-MB 231 cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02137	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	90	.	.	.	.	.	.	MDA-MB 435 cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02136	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	190	.	.	.	.	.	.	MDA-MB 435 cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02138	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	180	.	.	.	.	.	.	MDA-MB 435 cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02135	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	470	.	.	.	.	.	.	MDA-MB 435 cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02137	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	25	.	.	.	.	.	.	HUVEC cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02136	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	40	.	.	.	.	.	.	HUVEC cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02138	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	60	.	.	.	.	.	.	HUVEC cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02135	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	80	.	.	.	.	.	.	HUVEC cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02137	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	25	.	.	.	.	.	.	MCF-10A cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02136	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	40	.	.	.	.	.	.	MCF-10A cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02138	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	60	.	.	.	.	.	.	MCF-10A cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102528	PDC_02135	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Mean fluorescence intensities	100	.	.	.	.	.	.	MCF-10A cell	.	.	30 min	1 &mu;M	LSR Fortessa flow cytometer	"Next, we compared the breast cancer cell uptake of the two cyclic peptides,7and8(with alll-amino acids), versus the noncancerous cell uptake to three previously reported lead sequences (linear peptides), namely,1,2, and4. Two peptide concentrations were used, 1 &mu;M and 10 &mu;M. As shown inFigure S3, the magnitude of cell uptake increased considerably at higher peptide concentration (10 &mu;M). The intensity of cell-associated fluorescence at 10 &mu;M peptide concentration was at least 2-fold higher when compared to the cell-associated fluorescence observed at 1 &mu;M peptide concentration. This trend was observed for all breast cancer cell lines used in the study. The mean fluorescence intensities (MFIs) of FITC-7at 10 &mu;M were 2771 &plusmn; 78, 2607 &plusmn; 116, and 1761 &plusmn; 83 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively, whereas the MFIs were 179 &plusmn; 25 and 247 &plusmn; 27, respectively, when incubated with normal HUVEC and MCF10A. In comparison, the MFIs for the linear peptide with twod-amino acids x and k (FITC-4) were 965 &plusmn; 44, 1666 &plusmn; 97, and 1031 &plusmn; 54 when incubated with MCF-7, MDA-MB-231, and MDA-MB-435, respectively. Overall the uptake was observed in the following order1<2<4<7<8with peptide8displaying highest cellular uptake. Noncancerous cell uptake (HUVEC and breast tissue derived MCF-10A cells) of all the peptides was minimal. Even at high peptide concentration (10 &mu;M) the uptake of the peptides was low suggesting the presence of smaller number of putative receptors on these cells."	"Here we have designed cyclic analogues of peptide4to enhance the affinity and specificity toward breast cancer cell lines while maintaining the proteolytic stability. In addition, we have reduced the number ofd-amino acids from two to one or none, as it is hypothesized that cyclization may impart sufficient stability to the peptide structure. The results show that the cyclic peptide analogues display higher uptake by breast cancer cells than all other analogues tested so far, and show minimal uptake by the noncancerous cells. One of the cyclic analogues with oned-amino acid (7) was sufficiently stable toward proteolytic degradation. When immobilized on gold microcantilever surface, the peptide was able to capture breast cancer cells specifically. Preliminary animal studies using mice carrying orthotopic breast MDA-MB-231 tumors were also performed to track the Cy5.5 labeled peptide7in live mice. The study highlights the discovery of a novel proteolytically stable cyclic peptide7for breast cancer targeting that can be used for targeted drug delivery or for capturing circulating breast tumor cells from human blood samples."
REF102530	PDC_02142	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	746.8 &plusmn; 81.5 nM	nM	.	.	.	.	.	BT474cell	.	.	48 h	.	MTT assay	"Conjugate MAHNP-Dox was compared to Dox using HER2 positive breast cancer cell lines BT474 and SKBR3. Cellular toxicity analysis showed that MAHNP-Dox was more potent than free Dox, as indicated by lower IC50 values for both cell lines. The BT474 and SKBR3 cell lines had an IC50 of 746.8 &plusmn; 81.5 nM and 110.1 &plusmn; 12.7 nM for MAHNP-DOX and 2075.0 &plusmn; 368.0 nM and 172.9 &plusmn; 19.2 nM for Dox, respectively."	You et al. developed a unique approach for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A peptide fragment from the heavy chain 3 of the full-length antibody trastuzumab was obtained and termed AHNP. The 12-mer AHNP binds the extracellular domain of HER2 with high affinity and displays similar potency as trastuzumab. The peptide mimetic AHNP was then conjugated via an MMP-2 sensitive linker with doxorubicin (Dox) to form MAHNP-Dox conjugate essentially using ester/amide bonds.
REF102530	PDC_02142	Breast cancer	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	110.1 &plusmn; 12.7 nM	nM	.	.	.	.	.	SKBR3 cell	.	.	48 h	.	MTT assay	"Conjugate MAHNP-Dox was compared to Dox using HER2 positive breast cancer cell lines BT474 and SKBR3. Cellular toxicity analysis showed that MAHNP-Dox was more potent than free Dox, as indicated by lower IC50 values for both cell lines. The BT474 and SKBR3 cell lines had an IC50 of 746.8 &plusmn; 81.5 nM and 110.1 &plusmn; 12.7 nM for MAHNP-DOX and 2075.0 &plusmn; 368.0 nM and 172.9 &plusmn; 19.2 nM for Dox, respectively."	You et al. developed a unique approach for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A peptide fragment from the heavy chain 3 of the full-length antibody trastuzumab was obtained and termed AHNP. The 12-mer AHNP binds the extracellular domain of HER2 with high affinity and displays similar potency as trastuzumab. The peptide mimetic AHNP was then conjugated via an MMP-2 sensitive linker with doxorubicin (Dox) to form MAHNP-Dox conjugate essentially using ester/amide bonds.
REF102530; REF102531	PDC_02143	Neuroblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1790 nM	nM	.	.	.	.	.	CA20948cell	.	.	3 days	.	MTT assay	"Previously, a series of CPT-SSA conjugates were tested for their stability in phosphate buffer/rat plasma and in vitro inhibitory activity in tumor cell growth (data not shown). Two of these conjugates, JF-10-71 and JF-10-81, displaying higher and lower stability, respectively, were chosen for further experiments in serial tumor cell lines. Also, free CPT and SSA itself were tested as controls. The results (Table 1) show that the IC50 values increased compared with CPT to JF-10-81 and further to JF-10-71 with the exception of the CA20948 cells. CPT and both conjugates were particularly effective in SSTR2-overexpressing IMR32 cells displaying IC50 values 3.1, 64.13, and 282.50 nM, respectively. SSTR2-overexpressing CA20948 cells were poorly responsive to CPT itself (IC50, 3077 nM); however, its somatostatin conjugates were actually more potent (IC50: JF-10-81, 1790 nM; JF-10-71, 1363 nM). SSA itself exhibited little effect on growth of all tested cell lines even at doses up to 10<sup>-5</sup> M."	"In a previous study, we used a potent somatostatin analog (SSA) with high affinity for SSTR2 for attachment to an antisense peptide nucleic acid (PNA) directed against the n-myc oncogene and showed that PNA-SSA conjugates produced receptor-specific inhibition of cell growth. Cleavable-linker chemistry was then developed that allowed this approach to be extended to well-known cytotoxic compounds such as camptothecin and combretastatin. In the present report two CPT-SSA conjugates, JF-10-71 and JF-10-81, displaying differing stabilities were chosen to potentially treat SSTR2-positive rat pancreatic CA20948 tumors in Lewis rats and SCLC NCI-H69 tumors in athymic nude mice."
REF102530; REF102531	PDC_02144	Neuroblastoma	.	Revealed Based on the Cell Line Data	High Expreesion	Half maximal inhibitory concentration (IC50)	1363 nM	nM	.	.	.	.	.	CA20948cell	.	.	3 days	.	MTT assay	"Previously, a series of CPT-SSA conjugates were tested for their stability in phosphate buffer/rat plasma and in vitro inhibitory activity in tumor cell growth (data not shown). Two of these conjugates, JF-10-71 and JF-10-81, displaying higher and lower stability, respectively, were chosen for further experiments in serial tumor cell lines. Also, free CPT and SSA itself were tested as controls. The results (Table 1) show that the IC50 values increased compared with CPT to JF-10-81 and further to JF-10-71 with the exception of the CA20948 cells. CPT and both conjugates were particularly effective in SSTR2-overexpressing IMR32 cells displaying IC50 values 3.1, 64.13, and 282.50 nM, respectively. SSTR2-overexpressing CA20948 cells were poorly responsive to CPT itself (IC50, 3077 nM); however, its somatostatin conjugates were actually more potent (IC50: JF-10-81, 1790 nM; JF-10-71, 1363 nM). SSA itself exhibited little effect on growth of all tested cell lines even at doses up to 10<sup>-5</sup> M."	"In a previous study, we used a potent somatostatin analog (SSA) with high affinity for SSTR2 for attachment to an antisense peptide nucleic acid (PNA) directed against the n-myc oncogene and showed that PNA-SSA conjugates produced receptor-specific inhibition of cell growth. Cleavable-linker chemistry was then developed that allowed this approach to be extended to well-known cytotoxic compounds such as camptothecin and combretastatin. In the present report two CPT-SSA conjugates, JF-10-71 and JF-10-81, displaying differing stabilities were chosen to potentially treat SSTR2-positive rat pancreatic CA20948 tumors in Lewis rats and SCLC NCI-H69 tumors in athymic nude mice."